WO2009144632A1

WO2009144632A1 - Novel compounds

Info

Publication number: WO2009144632A1
Application number: PCT/IB2009/052105
Authority: WO
Inventors: Alan Daniel Brown; Wolfgang Klute; Duncan Charles Miller
Original assignee: Pfizer Limited
Priority date: 2008-05-30
Filing date: 2009-05-20
Publication date: 2009-12-03

Abstract

The present invention relates to a class of substituted purine compounds of formula (I), uses thereof, processes for the preparation thereof and compositions containing said compounds. These compounds have utility in a variety of therapeutic areas including sexual dysfunction.(I).

Description

Novel Compounds

The present invention relates to a class of substituted purine compounds with activity as CRF₁ receptor antagonists, uses thereof, processes for the preparation thereof and compositions containing said antagonists. These antagonists have utility in a variety of therapeutic areas including anxiety disorders; depression and stress related disorders; and sexual dysfunction, particularly female sexual dysfunction (FSD).

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Natl. Acad. Sci (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981 )]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioural effects consistent with a neurotransmitter or neuromodulator role in the brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); .F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41 :527 (1987)]. There is evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, as they relate to the dysfunction of CRF neurons in the central nervous system [for a review, see: E. B. De Souze, Hosp. Practice 23:59 (1988)]. Anxiety disorders are a group of diseases, recognized in the art that includes phobic disorders, anxiety states, post-traumatic stress disorder and atypical anxiety disorders [The Merck Manual of Diagnosis and Therapy, 16^th edition (1992)]. Emotional stress is often a precipitating factor in anxiety disorders, and such disorders generally respond to medications that lower response to stress. In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [CB. Nemeroff et al., Science 226:1342 (1984); CM. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [CB. Memeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P.W. Gold et al., Am. J. Psychiatry 141 :619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P.W. Gold et al., New Engl. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is also preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)]. CRF has also been implicated in the aetiology of anxiety-related disorders, and is known to produce anxiogenic effects in animals. Interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31 :363 (1982); CW. Berridge and A.J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41 ) in a variety of behavioral paradigms demonstrates that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [CW. Berridge and A.J. Dunn Horm. Behav. 21 :393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlodiazepoxide attenuates the "anxiogenic" effects of CRF both in the conflict test [KT. Britton et al., Psychopharmacology 86:170 (1985); KT. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist Ro 15-1788, which was without behavioural activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF [KT. Britton et al., Psychopharmacology 94:396 (1988)]. The mechanisms and sites of action through which conventional anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. Preliminary studies, examining the effects of a CRF₁ receptor antagonist peptide (α-helical CRF₉.₄₁) in a variety of behavioral paradigms, have demonstrated that the CRF₁ antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for a review, see: G. F. Koob and KT. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and CB. Nemeroff eds., CRC Press p.221 (1990)]. The use of CRF₁ antagonists for the treatment of Syndrome X has also been described in U.S. Patent Application No. 09/696,822, filed October 26, 2000, now issued as U.S. Patent No. 6,589,947and European Patent Application No. 003094414, filed October 26, 2000, which are also incorporated in their entireties herein by reference. Methods for using CRF₁ antagonists to treat congestive heart failure are described in U.S. Serial No. 09/248,073, filed February 10, 1999, now U.S. patent 6,043,260 (March 28, 2000) which is also incorporated herein in its entirety by reference. CRF is known to have a broad extrahypothalmic distribution in the CNS, contributing therein to a wide spectrum of autonomic behavioural and physiological effects [see, e.g., Vale et al., 1983; Koob, 985; and E. B. De Souze et al., 1985]. For example, CRF concentrations are significantly increased in the cerebral spinal fluid of patients afflicted with affective disorder or major depression [see, e.g., Nemeroff et al., 1984; Banki et al., 1987; France et al., 1988; Arato et al., 1989]. Moreover, excessive levels of CRF are known to produce anxiogenic effects in animal models [see, e.g., Britton et al., 1982; Berridge and Dunn, 1986 and 1987], and CRF₁ antagonists are known to produce anxiolytic effects; accordingly, therapeutically effective amounts of compounds provided herein may, for example, determined by assessing the anxiolytic effects of varying amounts of the compounds in such animal models. The present invention provides a compound of formula (I)

wherein:

R¹ and R² are independently selected from H, Me, CF₃, F, Cl, OCH₃, OC₂H₅, OCHF₂, OCF₃ and CN; or R¹ and R² when attached to adjacent carbon atoms are taken together to form

or ,wherein the arrow heads denote the point of attachment to the phenyl moiety;

R³ is H or F; with the proviso that when R¹ is Me, H or F, R² is not OCH₃;

or a pharmaceutically acceptable salt, solvate or polymorph thereof.

Me means methyl.

In one embodiment, R¹ is selected from OCH₃, OC₂H₅, OCF₃, and OCHF₂.

In a further embodiment, R¹ is selected from OCH₃ and OCHF₂

In yet a further embodiment, R¹ is OCHF₂ In one embodiment, R² is selected from Cl, OCH₃ and H.

In a further embodiment, R¹ is OCHF₂ and R² is selected from Cl, OCH₃ and H.

In one embodiment, R³ is H.

It is to be understood that the invention covers all combinations of particular embodiments of the invention as described hereinabove, consistent with the definition of the compounds of formula (I). Representative compounds of formula (I) are Examples 1 to 42.

Pharmaceutically acceptable salts of the compounds of formula (I) comprise the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate , glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid or base; or (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H.

G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non- stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, X7_, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J

Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975

Hereinafter all references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).

As indicated, so-called 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in

"Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and

"Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E. B. Roche, American

Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier,

1985).

An example of prodrugs in accordance with the invention include, where the compound of formula (I) contains a secondary amino functionality, an amide thereof, for example, a compound wherein the hydrogen of the amino functionality of the compound of formula (I) is replaced by (C-ι-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoing example and examples of other prodrug types may be found in the aforementioned references. Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I). Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include

(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof

(-CH₃ -> -CH₂OH): (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂);

(iv) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and Compounds containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.

Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, a keto group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition salts wherein the counterion is optically active, for example, d-lactate or /-lysine, or racemic, for example, c//-tartrate or dl- arginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically- enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

The present invention includes all crystal forms of the compounds of formula (I) including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic

Compounds" by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as H and H, carbon, such as C, C and C, chlorine, such as Cl, fluorine, such as

¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵ O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I). The invention includes all polymorphs of the aforementioned species and crystal habits thereof. When preparing compounds of formula (I) in accordance with the invention, it is open to a person skilled in the art to routinely select the form of intermediate which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995). The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V\_ (6), 981-986, by Liang and Chen (2001 ).

For tablet dosage forms, depending on dose, the drug may make up from 0.05 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower a Iky I -substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 2 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch , dibasic calcium phosphate dihydrate and anhydrous.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 61 and 65, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.1 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drug, from about 1 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 50 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends and granules may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (I) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1-14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(c//-lactic- coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I- leucine, microcrystalline cellulose, mannitol, and magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 10Oμl. A typical formulation may comprise a compound of formula (I ), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 2 to 30mg of the compound of formula (I). The overall daily dose will typically be in the range 50 to 100mg which may be administered in a single dose or, more usually, as divided doses throughout the day. The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/1 1172, WO 94/02518 and WO 98/55148. Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.5mg to 1000mg, for example 50mg to 250mg, depending, of course, on the mode of administration and efficacy. For example, oral administration may require a total daily dose of from 50mg to 1000mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier.

Processes

In the general processes, and schemes, that follow: R¹and R² are as previously defined in respect of a compound of formula (I) unless otherwise stated; LG is is a leaving group appropriate to aromatic nucleophilic substitution, such as those disclosed in Jerry March, Advanced Organic Chemistry (4th edition), Wiley Interscience, 1992, page 652 (incorporated herein by reference), e.g. F, Cl, Br, I, SO₂Me, OMe or OEt; boc is t-butoxycarbonyl. Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

Compounds of formula (I) may be prepared by any methods known for the preparation of compounds of analogous structure.

Compounds of formula (I), and intermediates thereto, may be prepared according to the schemes that follow.

It will be appreciated by those skilled in the art that certain of the procedures described in the schemes for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible substituents.

It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in the schemes in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I). It will be still further appreciated by those skilled in the art that, as illustrated in the schemes that follow, it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 7, pages 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups. Suitable guides to synthesis, functional group interconversions, use of protecting groups, etc., are for example: "Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989); Advanced Organic Chemistry" by J. March, Wiley lnterscience (1985); "Designing Organic Synthesis" by S Warren, Wiley lnterscience (1978); "Organic Synthesis - The Disconnection Approach" by S Warren, Wiley lnterscience (1982); "Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman (1982); "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); and "Protecting Groups" by PJ, Kocienski, Georg Thieme Verlag (1994); and any updated versions of said standard works.

Compounds of formula (I) may be prepared according to Scheme 1.

Scheme 1

With specific reference to Scheme 1 , steps (a) to (c) may be effected as follows:

Step (a) -Nucleophilic substitution

Compounds of formula (IV) may be prepared via displacement of a leaving group (LG) from the aminopyrimidine of formula (II) with the aniline of formula (III), in the presence of an acid, in a solvent. Typically, a solution of hydrochloric acid in ethanol is added to a stirred solution of the aminopyrimidine of formula (II) and the aniline of formula (III) in an alcoholic solvent, such as ethanol (EtOH) or 2- methoxy ethanol, at between ambient temperature and reflux for between 2h and 48hr; optionally heating may be effected to between ambient temperature and 16O⁰C under microwave conditions for between 0.25h and 2h. At least one equivalent of the intermediate aniline compound (III) and at least one equivalent of the acid are required; an excess of the acid may be optionally used. The intermediates (IV) were isolated as either the free base or the hydrochloride salt.

Step (b) -Cyclisation

Compounds of formula (V) may be prepared via cyclization of the compound of formula (IV) in the presence of a suitable orthoester such as trimethylorthoacetate or triethylorthoacetate under either basic or acidic conditions in a suitable solvent. Typically, a solution of the hydrochloride salt of the compound of formula (IV) is mixed with a solution of triethylamine in a suitable organic solvent such as acetonitrile or 1 ,4-dioxan, followed by addition of a suitable orthoester such as trimethylorthoacetate or triethylorthoacetate and warmed to reflux for between 3 and 48 hours. At least one equivalent of the intermediate compound of general formula (I), and an excess of both triethylamine and orthoester are required. Alternatively, the free base of the compound of formula (IV) is mixed with catalytic para toluenesulphonic acid (pTSOH) in ethanol (EtOH) or toluene (ToI) followed by addition of a suitable orthoester such as trimethylorthoacetate or triethylorthoacetate with subsequent heating to reflux. At least one equivalent of the intermediate compound of (IV), and an excess of orthoacetate are required. The intermediates (V) were obtained as either a mixture of the desired compound and the methoxy adduct or pure product compound.

A person skilled in the art will appreciate that alternative cyclisation methodologies may also be used to convert the compounds of formula ( IV) into the compounds of formula (V), for example coupling to an activated acid such as acetyl chloride with subsequent dehydratitive cyclisation.

Step (c) - Nucleophilic substitution

Compounds of formula (I) may be prepared via displacement of the leaving group LG from the compound of formula (V) with C,C-dicyclopropylmethylamine (Vl) in a suitable solvent, such as n-butanol or acetonitrile, in the presence of a base such as triethylamine or diisopropylethylamine. Typically, C,C-dicyclopropylmethylamine (Vl) is mixed with the compound of formula (V) in the presence of a base ( such as triethylamine), in n-butanol (nBuOH) and warmed to reflux for between 3 and 48 hours. At least one equivalent of the compound of formula (V), and at least one equivalent of C, C- dicyclopropylmethylamine (Vl) and base are required; optionally an excess of C, C- dicyclopropylmethylamine (Vl) and based may be used.

Alternatively, C,C-dicyclopropylmethylannine (Vl) is mixed with the compound of formula (V) optionally in the presence of a suitable base (such as diisopropylethylamine) in acetonitrile (MeCN) and warmed under microwave conditions to 16O⁰C for between 0.25 and 2 hours. At least one equivalent of the compound of formula (V), and an excess of intermediate (Vl) and diisopropylethylamine should be used.

Compounds of formula (I) may also be prepared according to Scheme 2.

Scheme 2

With specific reference to Scheme 2, steps (d) to (g) may be effected as follows:

Step (d) -Nucleophilic substitution

Compounds of formula (VII) may be prepared via displacement of a leaving group (LG) from the aminopyrimidine of formula (II) with ammonia under heating in a sealed vessel. Typically, the aminopyrimidine of formula (II) and 0.880 NH₃ are heated at between 50 and 150⁰C in a sealed vessel for between 10 minutes and 24 hours. Optionally heating may be effected under microwave conditions.

Step (e) -Cyclisation

Compounds of formula (VIII) may be prepared via cyclization of the compound of formula (VII) in the presence of a suitable orthoester, such as trimethylorthoacetate or triethylorthoacetate, and acetic anhydride under either basic or acidic conditions in a suitable solvent. Typically, a compound of the formula (VII) is dissolved in acetic anhydride followed by addition of a suitable orthoester such as trimethylorthoacetate or triethylorthoacetate and warmed to between 50 and

120⁰C for between 2 and 48 hours. Typically an excess of both acetic anhydride and the orthoester are employed.

A person skilled in the art will appreciate that alternative cyclisation methodologies may also be used to convert the compounds of formula (VII) into the compounds of formula (VIII), for example coupling to an activated acid such as acetyl chloride with subsequent dehydratitive cyclisation and acetylation.

Step (f) - Nucleophilic substitution

Compounds of formula (IX) may be prepared via displacement of the leaving group LG from the compound of formula (VIII) with C,C-dicyclopropylmethylamine (Vl) in a suitable solvent, such as n- butanol, or acetonitrile in the presence of a base such as triethylamine or diisopropylethylamine. Typically, C,C-dicyclopropylmethylamine (Vl) is mixed with the compound of formula (VIII) in the presence of a base (such as triethylamine), in n-butanol (nBuOH) and warmed to reflux for between 3 and 48 hours. At least one equivalent of the compound of formula (VIII), and at least one equivalent of C,C-dicyclopropylmethylannine (Vl) and base are required; optionally an excess of C, C- dicyclopropylmethylamine (Vl) and base may be used.

Alternatively, C,C-dicyclopropylmethylamine (Vl) is mixed with the compound of formula (VIII) optionally in the presence of a suitable base (such as diisopropylethylamine) in acetonitrile (MeCN) and warmed under microwave conditions to 16O⁰C for between 0.25 and 2 hours. At least one equivalent of the compound of formula (V), and an excess of intermediate (VIII) and diisopropylethylamine should be used.

Step (g)- Arylation of purine core

Compounds of the formula (I) may be prepared from compounds of the formula (IX) via displacement of a suitable leaving group from an aromatic group of the formula (X) (preferably R¹, R² or R³ is an electron withdrawing group), in the presence of a suitable solvent such as DMSO or 1 ,4-dioxan and a suitable base such as Cs₂CO₃ or K₂CO₃. An example of a particularly suitable leaving group for a compound of the formula (X) is fluorine.

Typically one equivalent of a compound of the formula (IX) and at least one equivalent of a compound of the formula (X) are dissolved in DMSO in the presence of between 1 and 5 equivalents of a base (such as Cs₂CO₃) and heated for between 10 minutes and 24 hours at between 80 and 150⁰C. Heating may be effected conventionally or through microwave irradiation.

Alternatively compounds of the formula (I) may be prepared from compounds of the formula (IX) according to Scheme 3.

Scheme 3

With specific reference to Scheme 3, step (h) may be effected as follows:

Step (h)- Arylation of purine core Compounds of the formula (I) may be prepared from compounds of the formula (IX) via metal mediated coupling to a suitable aromatic (Xl) substituted with a group (Y), which is amenable to metal insertion such as Br, I or triflate, in the presence of a suitable solvent such as DMF or 1 ,4-dioxan and a suitable base such as Cs₂CO₃ or K₂CO_3, a suitable metal source such as copper (I) iodide and a suitable ligand such a 1 ,10 phenanthroline. Typically one equivalent of a compound of the formula (IX) and one to five equivalents of a compound of the formula (Xl) are dissolved in DMF in the presence of between 1 and 5 equivalents of a CuI, one to five equivalents of a base such as Cs₂CO₃, and one to five equivalents of a ligand such as 1 ,10 phenanthroline and heated for between 2 and 48 hours at between 80 and 150⁰C. Heating may be effected conventionally or through microwave irradiation. A person skilled in the art will recognise that other methods for coupling a substituted aromatic to a purine heterocycle may be applicable, including metal catalysed coupling to aryl boronic acids, for example as described in European Journal of Organic Chemistry, Volume 2005, Issue 24 (p 5154-5157) and other metal catalysed coupling procedures for aryl halides such as those outlined in J. C. Antilla, J. M. Baskin, T.E. Barder and S. L. Buchwald, J. Org. Chem. 69 (2004), p. 5578; J. C. Antilla, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc. 124 (2002), p. 11684; A. Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem. Soc. 123 (2001 ), p. 7727; A. Kiyomori, J. F. Marcoux and S. L. Buchwald, Tetrahedron Lett. 40 (1999), p. 2657; P.Y.S. Lam, S. Deudon, K.M. Averill, R. Li, M.Y. He, P. DeShong and CG. Clark, J. Am. Chem. Soc. 122 (2000), p. 7600; H.J. Cristau, P.P. Cellier, J. F. Spindler and M. Taillefer, Eur. J. Org. Chem. (2004), p. 695; H.J. Cristau, P.P. Cellier, J. F. Spindler and M. Taillefer, Chem. Eur. J. 10 (2004), p. 5607; BoIm, Angew. Chem., Int. Ed., 2007, 46, 8862 or Taillefer, Angew. Chem. Int. Ed., 2007, 46, 934

Compounds of formula (I) may also be prepared by functional group interconversion under conventional conditions. For example, compounds of formula (I) wherein R¹ or R² is OMe or OCH₂F may be prepared from the corresponding phenol; wherein R¹ or R² is OMe or CN may be prepared from the corresponding aryl bromide; and wherein R¹, R² or R³ is OMe may be prepared from the corresponding aryl fluoride.

Compounds of formula (II), (III), (Vl), (X) and (Xl) are either commercially available or will be well -known to those skilled in the art with reference to literature precedents and/or the preparations herein. A skilled person will appreciate that compounds of formula (III) may also be prepared by functional group interconversion under conventional conditions. For example, compounds of formula (III) wherein R¹ or R² is OMe or OCH₂F may be prepared from the corresponding phenol; wherein R¹ or R² is OMe or CN may be prepared from the corresponding aryl bromide; wherein R¹, R² or R³ is OMe may be prepared from the corresponding aryl fluoride; and the amine compounds of formula (III) may also be prepared from the corresponding nitro substituted compounds.

Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formulae (IV), (V), (VII), (VIII) and (IX) are key intermediates and represent a particular aspect of the present invention.

All of the above reactions and the preparations of novel starting materials disclosed in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

The compounds of the invention are useful because they have pharmacological activity in animals. More particularly, they are useful in the treatment or prevention of a disorder in which modulation of CRF-1 receptor stimulation could provide a beneficial effect, including anxiety disorders; depression and stress related disorders; and sexual dysfunction, particularly female sexual dysfunction (FSD). The compounds of the invention are useful for treating various disorders in a mammal, particularly in a human, such as social anxiety disorder; panic disorder; obsessive-compulsive disorder; anxiety with co- morbid depressive illness; affective disorder; anxiety; depression; irritable bowel syndrome; posttraumatic stress disorder; supranuclear palsy; immune suppression; gastrointestinal disease; anorexia nervosa or other feeding disorder; drug or alcohol withdrawal symptoms; substance abuse disorder (e.g., nicotine, ***e, ethanol, opiates, or other drugs); inflammatory disorder; fertility problems; disorders the treatment of which can be effected or facilitated by antagonizing CRF₁ including but not limited to disorders induced or facilitated by CRF; a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; skin disorders such as acne and psoriasis; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependences on alcohol, ***e, heroin, benzodiazepines, or other drugs); osteoporosis; psychosocial dwarfism and hypoglycemia.

In the present specification, the term "animal" refers to humans (female or male), companion animals (e.g., dogs, cats and horses), edible animals, zoo animals, marine animals, birds and other similar animal species. "Edible animals" refers to food-source animals such as cows, pigs, sheep and poultry.

Accordingly in another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament.

In another aspect the invention provides a method of treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect, in an animal, in particular a human, comprising administering to said animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof.

In another aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect.

In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use in the treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect. In another aspect the invention provides a method of treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect, in an animal, in particular a human, comprising administering to said animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein the disorder or condition is selected from sexual dysfunction, female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, anxiety with co-morbid depressive illness, affective disorder, anxiety, eating disorders, bipolar disorder and depression.

In another aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect, wherein the disorder or condition is selected from sexual dysfunction, female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, anxiety with co-morbid depressive illness, affective disorder, anxiety, eating disorders, bipolar disorder and depression.

In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use in the treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect, wherein the disorder or condition is selected from sexual dysfunction, female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, anxiety with co-morbid depressive illness, affective disorder, anxiety, eating disorders, bipolar disorder and depression.

Sexual dysfunction (SD) is a significant clinical problem which can affect both males and females. The causes of SD may be both organic as well as psychological. Organic aspects of SD are typically caused by underlying vascular diseases, such as those associated with hypertension or diabetes mellitus, by prescription medication and/or by psychiatric disease such as depression. Physiological factors include fear, performance anxiety and interpersonal conflict. SD impairs sexual performance, diminishes self- esteem and disrupts personal relationships thereby inducing personal distress. In the clinic, SD disorders have been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (Melman et al, J. Urology, 1999, .161, 5-11 ).

FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, S. R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 1(), S104-S106; Berman, J. R., Berman, L. & Goldstein, I. (1999). Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options. Urology, 54, 385-391 ). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse or a combination of these problems. Several types of disease, medications, injuries or psychological problems can cause FSD, for example, antidepressant-induced female sexual dysfunction (Seqraves RT., Antidepressant-induced sexual dysfunction. J CHn Psychiatry. 1998;59 Suppl 4:48-54.; Taylor MJ., Strategies for managing antidepressant-induced sexual dysfunction: a review, Curr Psychiatry Rep. 2006 Dec;8(6):431-6).Treatments in development are targeted to treat specific subtypes of FSD, predominantly desire and arousal disorders.

The categories of FSD are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (Leiblum, S. R. (1998). Definition and classification of female sexual disorders, Int. J. Impotence Res., 10, S104-S106). Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli. Arousal is the vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity. Orgasm is the release of sexual tension that has culminated during arousal. Hence, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm. FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders. Although the compound of formula (I) will restore the genital response and improve subjective arousal in response to sexual stimulation (as in female sexual arousal disorder), in doing so it may also improve the associated pain, distress and discomfort associated with intercourse and so treat other female sexual disorders. Thus, in accordance with a further aspect of the invention, there is provided the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, preferably for the treatment or prophylaxis of hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder, more preferably for the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder, and sexual pain disorder, and most preferably in the treatment or prophylaxis of sexual arousal disorder.

Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety. Female sexual arousal disorder (FSAD) is characterised by inadequate genital response to sexual stimulation. The genitalia do not undergo the engorgement that characterises normal sexual arousal. The vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded. Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes, hypertension, and atherosclerosis. Other causes result from treatment with diuretics, antihistamines, antidepressants eg SSRIs or antihypertensive agents.

Sexual pain disorders (includes dyspareunia and vaginismus) may be characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems but may also include noncoital sexual pain.. The prevalence of FSD is difficult to gauge because the term covers several types of problem, some of which are difficult to measure; such problems are typically poorly reported by the women experiencing them; and because the interest in treating FSD is relatively recent. Many women's sexual problems are associated either directly with the female ageing process or with chronic illnesses such as diabetes and hypertension. Clinical assessment and diagnosis tools are reviewed by Althof et al in J. Sex Med 2005, 2(Suppl. 3), pp-146-153.

Because FSD consists of several subtypes that express symptoms in separate phases of the sexual response cycle, there is not a single therapy. Current treatment of FSD focuses principally on psychological or relationship issues. Treatment of FSD is gradually evolving as more clinical and basic science studies are dedicated to the investigation of this medical problem. Female sexual complaints are not all psychological in pathophysiology, especially for those individuals who may have a component of vasculogenic dysfunction (eg FSAD) contributing to the overall female sexual complaint. There are at present no drugs licensed for the treatment of FSD. Empirical drug therapy includes oestrogen administration (topically or as hormone replacement therapy), androgens or mood-altering drugs such as buspirone or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects.

The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines Female Sexual Arousal Disorder (FSAD) as being:

"a persistent or recurrent inability to attain or to maintain until completion of the sexual activity adequate lubrication-swelling response of sexual excitement. The disturbance must cause marked distress or interpersonal difficulty."

The arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The disturbance causes marked distress and/or interpersonal difficulty. Basson et al ( J. Urology, 2000, 163, 888-893, incorporated herein by reference) describes a revised classification system which follows the same general structure as DSM IV wherein the four major categories of dysfunction, that is desire (including hypoactive sexual desire disorder and sexual aversion disorder), arousal, orgasmic and sexual pain disorders are preserved and a new category of sexual pain including non-coital sexual pain is described. Non-coital sexual pain disorder is recurrent or persistent genital pain induced by non-coital sexual stimulation. FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post menopausal (±HRT) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and urogenital disorders.

The primary consequences of FSAD are lack of engorgement/swelling, lack of lubrication and lack of pleasurable genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm.

Male sexual dysfunction (MSD) is generally associated with either erectile dysfunction, also known as male erectile dysfunction (MED) and/or ejaculatory disorders such as premature ejaculation, anorgasmia (unable to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (lack of interest in sex). It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

The compounds of formula (I) may be co-administered with one or more agents selected from:

1) Cholesterol lowering agents such as statins (e.g. atorvastatin/ Lipitor- trade mark) and fibrates;

2) Estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5, 6,7,8- tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof the preparation of which is detailed in WO 96/21656;

3) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (i.e. as a combination), or estrogen and methyl testosterone hormone replacement therapy agent (e.g. HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo,

Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone);

4) Testosterone replacement agents, including dehydroandrostendione, testosterone (including Tostrelle and Intrinsa), dihydrotestosterone or a testosterone implant;

5) Serotonin receptor agonists, antagonist or modulator, more particularly agonists, antagonists or modulators for 5HT1A (including VML 670 [WO02/074288], flibanserin [US2003/0104980] and OPC 14523 [US2007/0142395]), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993;

6) melanocortin receptor agonists or modulators (including PT-141 [Bremelanotide] and melanotan- Il and preferably a selective MCR3, MCR3/4 and/or MCR4 melanocortin agonist or modulator (including MB-243 , RO0282425 and the compounds described in WO2005/77935 and PCT/IB07/000456); and

7) PDE inhibitors such as PDE2 (e.g. erythro-9-(2-hydroxyl-3-nonyl)-adenine) and Example 100 of EP 0771799-incorporated herein by reference) and in particular a PDE5 inhibitor such as the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7- ones disclosed in EP-A-0526004; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d]pyrimidin-4-ones disclosed in published international patent application WO 93/07149; the quinazolin-4-ones disclosed in published international patent application WO 93/12095; the pyrido [3,2-d]pyrimidin- 4-ones disclosed in published international patent application WO 94/05661 ; the purin-6-ones disclosed in published international patent application WO 94/00453; the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in published international patent application WO 98/49166; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 99/54333; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751 ; the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in published international patent application WO 00/24745; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; the compounds disclosed in published international application WO95/19978; the compounds disclosed in published international application WO 99/24433 and the compounds disclosed in published international application WO 93/07124; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/271 12; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/271 13; the compounds disclosed in EP-A-1092718 and the compounds disclosed in EP-A-1092719.

The contents of the published patent applications and journal articles and in particular the general formulae of the therapeutically active compounds of the claims and exemplified compounds therein are incorporated herein in their entirety by reference thereto.

Preferred agents for coadministration with the compounds of the present invention are PDE5 inhibitors. The suitability of any particular cGMP PDE5 inhibitor can be readily determined by evaluation of its potency and selectivity using literature methods followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc in accordance with standard pharmaceutical practice.

IC50 values for the cGMP PDE5 inhibitors may be determined using the PDE5 assay described in WO01/271 13.

Preferably the cGMP PDE5 inhibitors used in the pharmaceutical combinations according to the present invention are selective for the PDE5 enzyme. Preferably (when used orally) they are selective over PDE3, more preferably over PDE3 and PDE4. Preferably (when oral), the cGMP PDE5 inhibitors of the invention have a selectivity ratio greater than 100 more preferably greater than 300, over PDE3 and more preferably over PDE3 and PDE4.

Selectivity ratios may readily be determined by the skilled person. IC50 values for the PDE3 and PDE4 enzyme may be determined using established literature methodology, see S A Ballard et al, Journal of Urology, 1998, vol. 159, pages 2164-2171.

Suitable cGMP PDE5 inhibitors for the use according to the present invention include:

The pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d]pyrimidin-4-ones disclosed in published international patent application WO 93/07149; the quinazolin-4-ones disclosed in published international patent application WO 93/12095; the pyrido [3,2-d]pyrimidin-4-ones disclosed in published international patent application WO 94/05661 ; the purin-6-ones disclosed in published international patent application WO 94/00453; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 98/49166; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 99/54333; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751 ; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 00/24745; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; the hexahydropyrazino [2',1':6,1]pyrido [3,4-b]indole-1 ,4-diones disclosed in published international application WO95/19978; the imidazo[5,1 - f][1 ,2,4]triazin-ones disclosed in EP-A-1092719 and in published international application WO 99/24433; and the bicyclic compounds disclosed in published international application WO 93/07124; all of which are incorporated herein by reference.

Further examples of suitable PDE5 inhibitors for use herein include: the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/271 12; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/271 13; the compounds disclosed in EP-A- 1092718 and the compounds disclosed in EP-A-1092719; the tricyclic compounds disclosed in EP-A- 1241170; the alkyl sulphone compounds disclosed in published international application WO 02/074774; the compounds disclosed in published international application WO 02/072586; the compounds disclosed in published international application WO 02/079203; the compounds described in WO01187882; the compounds described in WO0056719, e.g. BMS-341400; the compounds described in WO9964004, e.g. BMS-263504; the compounds described in EP-1057829 (Jordanian Pharmaceutical Manufacturing and Medical Equipment Company); the compounds described in EP722936; the compounds described in WO93/07124; the compounds described in WO98/06722; the compounds described in WO98/06722; the compounds described in EP579496 and in particular ONO1505 (Ono); the compounds described in WO97/03070 and in particular OPC35564 (Otsuka); and the compounds described in WO02/074312; all of which are incorporated herein by reference.

Yet further examples of suitable PDE5 inhibitors for use herein include the carboline derivatives described in WO03000691 , WO02098875, WO02064591 , WO02064590 and WO0108688, the pyrazino [1',2':1 ,6] pyrido [3,4-B] indole 1 ,4-dione derivatives described in WO02098877, the tetracyclic compounds described in WO02098428, the compounds described in WO02088123 and WO0200656, the condensed pyrazindione derivatives described in WO0238563 and WO02000657, the indole derivatives described in WO0236593, the condensed pyrindole derivatives described in WO0228865 and WO0228859, the hexahydropyrazino[1 ',2':1 ,6]-pyrido [3,4-B] indole-1 ,4-dione derivatives described in WO0228858 and WO0194345, the fused heterocyclic derivatives described in WO0210166, the cyclic GMP specific phosphodiesterase inhibitors described in WO0200658, the tetracyclic diketopiperazine compounds described in WO0194347, the compounds described in WO0298877 and the compounds described in use application WO0219213, all of which are incorporated herein by reference.

Yet further examples of suitable PDE5 inhibitors for use herein include the compounds described in WO0164192, DE 10104800, WO0259126, DE10104095, WO0249651 , DE10063224, DE10060338, DE10058662 and WO0200660, all of which are incorporated herein by reference. Still other PDE5 inhibitors inhibitors useful in conjunction with the present invention include:

4-bronno-5-(pyridylnnethylannino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyrid azinone; i-^-KI .S-benzodioxol-S-ylmethylJaminol-β-chloro^-quinozolinyll^-piperidine-carboxylic acid,monosodiunn salt;

(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylnnethyl-5-nnethyl-cyclopent-4,5]innidazo[2,1- b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-innidazo[2,1-b]purin-4-one;

3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6- carboxylate; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;

4-bromo-5-(3-pyridylnnethylannino)-6-(3-(4-chlorophenyl) propoxy)-3(2H)pyridazinone;

1-nnethyl-5(5-nnorpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1 ,6-dihydro-7H-pyrazolo(4,3-d)pyrinnidin-

7-one; i-^-^I .S-benzodioxol-S-ylmethy^arninol-θ-chloro^-quinazolinyll^-piperidinecarboxylic acid, monosodium salt;

Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No.

5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); ER-118585, E-

8010, E-4021 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); FR181074, FR229934 and FR226807

(Fujisawa); TA-1032, T-0156 and TA-1790 (Tanabe Seiyaku); EMD82639 and EMR6203 (Merck); LAS34179 and LAS35917 (Almirall); Sch-51866; BMS-223131 (Bristol Myers Squibb); NCX911 (Nicox); and ABT-724 and ABT-670 (Abbott).

Preferred PDE5 inhibitors for the use according to the present invention include:

(i)

5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (sildenafil) also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine (see EP-A-0463756);

(ii)

S^-ethoxy-S-morpholinoacetylpheny^-i-methyl-S-n-propyl-i .θ-dihydro^H-pyrazolo^.S-dlpyrimidin^- one (see EP-A-0526004);

(iii) 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (see WO98/49166);

(iv)

3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridine-3-yl]-2-(pyridin-2-yl)methyl-2,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO99/54333); (V)

(+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl- 2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 3-ethyl-5-{5-[4-ethylpiperazin-1- ylsulphonyl]-2-([(1 R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one (see WO99/54333);

(vi)

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7- oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine (see WO01/271 13, Example

8);

(vii)

5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113, Example 15);

(viii)

5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (see WO 01/27113, Example 66);

(ix)

5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (see WO 01/271 12, Example 124);

(X)

5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one (see WO 01/27112, Example 132);

(xi)

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- pyrazino[2',1 ':6,1]pyrido[3,4-b]indole-1 ,4-dione (tadalafil, IC-351 , Cialis®), i.e. the compound of examples 78 and 95 of published international application WO95/19978, as well as the compound of examples 1 , 3, 7 and 8;

(xii)

2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1 ,2,4]triazin-4-one (vardenafil) also known as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]- as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine, i.e. the compound of examples 20, 19, 337 and 336 of published international application WO99/24433; (xiii) the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in WO00/27848, in particular N-[[3-(4,7-dihydro-1-methyl- 7-oxo-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl)-4-propoxyphenyl]sulfonyl]-1-nnethyl-2- pyrrolidinepropanamine [udenafil, DA-8159 (Example 68 of WO00/27848)];

(xiv) the compound of example 11 of published international application WO93/07124;

(XV) 4-(4-chlorobenzyl)amino-6,7,8-trimethoxyquinazoline;

(xvi) 7,8-dihydro-8-oxo-6-[2-propoxyphenyl]-1H-imidazo[4,5-g]quinazoline;

(xvii)

1-[3-[1-[(4-fluorophenyl)methyl]-7,8-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl]-4- propoxyphenyl]carboxamide;

(xviii) 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-

7-one;

(xix)

1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3- pyridylsulfonyl}-4-ethylpiperazine; and (XX)

7-(3-bromo-4-methoxyphenylmethyl)-1-ethyl-8-{[(1R,2R)- 2-hydroxycyclopropyl]amino}-3-(2- hydroxyethyl)-3,7-dihydro- 1H-purine-2,6-dione [dasantafil, SCH-446132]

;and

pharmaceutically acceptable salts and solvates thereof.

By cross reference herein to compounds contained in patents and patent applications which can be used in accordance with invention, we mean the therapeutically active compounds as defined in the claims (in particular of claim 1 ) and the specific examples (all of which is incorporated herein by reference).

If a combination of active agents is administered, then they may be administered simultaneously, separately or sequentially.

The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. The present invention provides for a composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier. In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salts, solvates or polymorphs thereof, a pharmaceutically acceptable diluent or carrier, and one or more additional therapeutic agents.

A suitable assay for determining the CRF₁ antagonist activity of a compound is detailed herein below:

CRF DiscoverX Reporter assay to measure functional activity of the CRF-1 Receptor

Recombinant human CRF-1 , cloned into CHO cells (Cell Sciences SNB0000377) were grown in DMEM:F12 (1 :1 ) media containing 10% (V/V) Foetal Bovine Serum (PAA), 400μg/ml Geneticin (GIBCO- BRL 10131-027) and 1 % (V/V) Glutamax in a cell incubator at 37⁰C, 5% CO₂. Cells were harvested at 70% confluence, media was removed and the cells were washed with warm phosphate buffered saline (PBS) solution. The cells were harvested using Cell Dissociating Solution (Sigma C5914) and then counted on a Cedex cell counter. The cells stock was adjusted to 2x10⁶ cells/ml using PBS containing IBMX (500 μM Final Assay Concentration). Compounds and controls were added to a 384 well Lumitrac 2000 plate (Greiner) as follows: 5μl PBS with 0.0167% Pluronic F-127 and 0.83% DMSO containing either 16.7μM 8-[butyl(ethyl)amino]-4-(2,6- dimethoxypyridin-3-yl)-6-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(7/-/)-one (Max inhibition control; J Med Chem 2004, 47(23): 5783), no addition (Min inhibition control) or test compound. To each well in the microtitre plate, 5μl agonist 10 nM FAC hCRF in PBS with 0.05% (V/V) Pluronic F-127 was added. Then 5μl cell suspension as described above was added to give 10,000 cells/well. The plate was then centrifuged at IOOOrpm 30 seconds and then incubated at 37°C for 90 min covered by a black low evaporation Nd.

After the incubation period, the cAMP response was measured using the DiscoveRx HitHunter cAMP Il Assay kit (Amersham Biosciences - 90-0034-03). To each well, 20μl of both DiscoveRx reagents was added. The plate was then sealed using an adhesive plate seal and centrifuged at IOOOrpm for 30 seconds. The plate was then gently vibrated using an orbital plate shaker for 90 min. The cAMP luminescence signal was then read after 4h using an LJL Analyst.

Each compound was tested multiple times using a 0.5 log serial dilution dose response with a top final assay concentration of 20 μM. Test compound %response values were calculated by normalising the test luminescence response using the average Max and Min control response on each plate. The %response of the test compound at different test doses were then fitted to a 4-parameter logistic curve to determine the compound IC50. K, values were determined from the IC50 using the Cheng and Prussoff relationship and the EC₅₀ for the agonist does response curve which was determined on the same day.

Using the assay described above, the exemplified compounds of the present invention all exhibit CRF₁ antagonist activity, expressed as a Ki value, of less than 10μM. Ki values for Examples 1 to 42 are shown in Table 1 Table 1 : Ki data

PREPARATIONS AND EXAMPLES

The Preparations and Examples that follow illustrate the invention but do not limit the invention in any way. All starting materials are available commercially or described in the literature. All temperatures are in ⁰C. Flash column chromatography was carried out using Merck silica gel 60 (9385). Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). "R_f" represents the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate. Melting points were determined using a Gallenkamp MPD350 apparatus and are uncorrected. NMR was carried out using a Varian-Unity Inova 400MHz NMR spectrometer or a Varian Mercury 400MHz NMR spectrometer. Mass spectroscopy was carried out using a Finnigan Navigator single quadrupole electrospray mass spectrometer or a Finnigan aQa APCI mass spectrometer.

Where it is stated that compounds were prepared in the manner described for an earlier Preparation or Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

APCI atmospheric pressure chemical ionisation mass spectrum br broad

CH₂CI₂ Dichloromethane δ chemical shift d doublet

DMF N,N-Dimethylformamide

ESI electrospray ionisation

EtOAc Ethyl Acetate

EtOH Ethanol

HCI Hydrochloric acid

HPLC high pressure liquid chromatography

LRMS low resolution mass spectrum m multiplet

Me methyl MgSO₄ Magnesium Sulphate

MTBE Methyl terfbutyl ether m/z mass spectrum peak

NaHCO₃ Sodium hydrogen carbonate

Na₂SO₄ Sodium sulphate

NMR nuclear magnetic resonance pTSOH para toluene sulphonic acid q quartet

Rt retention time

S singlet soln. solution t triplet

TFA Trifluoroacetic acid tic thin layer chromatography

For the avoidance of doubt, named compounds used herein have been named using ACD Labs Name Software v7.1 1 ™.

Where singleton compounds are analysed by LCMS, there are six methods used, shown below. System 1 : LCMS 6min run Basic run:

A: 0.1 % ammonium hydroxide in water B: 0.1 % ammonium hydroxide in acetonitrile Column: C18 phase Fortis 50 x 4.6mm with 5 micron particle size Gradient: 95-5% A over 3min, 1 min hold, 1 ml/min UV: 210nm - 450nm DAD Temperature: 5OC

System 2: LCMS 2 minute run Acid run:

A: 0.1 % formic acid in water B: 0.1 % formic acid in acetonitrile

Column: C18 phase Fortis Pace 20 x 2.1 mm with 3 micron particle size Gradient: 70-2% A over 1.8min, 0.2 min hold, 1.8ml/min UV: 210nm - 450nm DAD Temperature: 75C

System 3: (Mass Spec) ESCi: MS

Solvent 2OmM Ammonia 1 minute run System 4: LCMS 6m in run Acid run:

A: 0.1 % formic acid in water

B: 0.1 % formic acid in acetonitrile Column: C18 phase Phenomenex Luna 50 x 4.6mm with 5 micron particle size Gradient: 95-5% A over 3min, 1 min hold, 1 ml/min UV: 210nm - 450nm DAD Temperature: 5OC

System 5: LCMS 4min run Basic run:

A: 100% water

B: 1OmM ammonium bicarbonate in water Column: Xbridge C18 5um 2.1x30mm Gradient 100% A to 95%A:5%B over 3 min, 1 min hold, 1 ml/min

UV: 200nm - 350nm Temperature: 3OC

System 6: LCMS 4m in run A: 100% water B: Acetontrile

C: 1OmMoI ammonium bicarbonate Column: Xbridge C18 5um 3.0x150mm Gradient Time 0: 95%C:5%B

Time 15min: 95%B:5%C

Time 25 min: 5%B:95%C, hold 15 min

UV: 200nm - 350nm Temperature: 3OC

Where singleton compounds are purified by preparative HPLC, there are six methods used, shown below.

Method a Method b

Sunfire C18 4.6 x 50 mm id Xterra 4.6 x 50 mm id

Column column column Temperature Ambient Ambient

0.05% formic

Mobile Phase A acid in water 0.05% ammonia in

0.05% formic acid in 0.05% ammonia in

Mobile Phase B acetonitrile acetonitrile

Mobile Phase C

Gradient - Initial 5% B 5% B

Time 0 mins 5% B 5% B

Time 3 mins 98% B 98% B

Time 4 mins 98% B 98% B

Time 4.1 mins 5% B 5% B

Time 5 mins 5% B 5% B

Flow rate 1.5 ml / min 1.5 ml / min

Injection volume 5 ul 5 ul

Method c

Phenomenex

Luna 10u C18(2)

Column 150 x 21.2 (mm) 10 micron

Temperature Ambient

Mobile Phase A H₂O

Mobile Phase B MeCN

Mobile Phase C 2% Formic acid (aq)

Gradient - Initial A=90% B=5% C=5%

Time 0 mins A=90% B=5% C=5%

Time 0.6 mins A=90% B=5% C=5%

Time 8.5 mins A=5% B=90% C=5%

Time 11.5 mins A=5% B=90% C=5%

Time 11.6 mins A=90% B=5% C=5%

Time 14 mins A=90% B=5% C=5%

Flow rate 25 ml/min

Method d Method e Method f

Column Xterra Sunfire C18 19 x 100 Xterra C18 5um 19 x 100 mm mm id column, 5um C18 5um 19 x 100 mm

Temperature Ambient Ambient Ambient Mobile Phase A H₂O + 0.1 % DEA H₂O + 0.1 % formic acid H₂O + 0.1 % DEA

MeCN + 0.1 % formic

MeCN + 0.1 % DEA MeCN + 0.1 % DEA

Mobile Phase B acid Gradient - Initial A= 95%, B=5% A= 95%, B=5% A=60%, B=40% Time 0 mins A= 95%, B=5% A= 95%, B=5% A=60%, B=40% Time 1 min A= 95%, B=5% A= 95%, B=5% A=60%, B=40% Time 7 min A= 2%, B=98% A= 2%, B=98% A=5%, B=95% Time 9 min A= 2%, B=98% A= 2%, B=98% A=5%, B=95% Time 9.1 min A= 95%, B=5% A= 95%, B=5% A=60%, B=40% Time 10min A= 95%, B=5% A= 95%, B=5% A=60%, B=40% Flow rate 18ml/min 18ml/min 18ml/min Injection vol 100OuI 100OuI

For the compounds prepared by library synthesis, three LCMS methods were used on an Agilent 1956A mass spectrometer.

System A

Column Ymc ODS-AQ 2.0jA50mm 5um

Temperature 50 Degree Centigrade

Mobile Phase A 0.0375% TFA in water (v/v) Mobile Phase B 0.01875% TFA in acetonitrile (v/v)

Gradient - Initial 10% B

Time 0 mins 10% B

Time 0.5 mins 10% B

Time 4 mins 100% B Time 4.3 mins 10% B

Time 4.7 mins 10% B

Flow rate 0.8 ml / min

Injection volume 2 ul

System B

Column Ymc ODS-AQ 2.0jA50mm 5um Temperature 50 Degree Centigrade Mobile Phase A 0.0375% TFA in water (v/v) Mobile Phase B 0.01875% TFA in acetonitrile (v/v) Gradient - Initial 1 % B Time 0.0 mins 1 % B Time 0.6 mins 5% B Time 4.0 mins 100% B Time 4.3 mins 1 % B Time 4.7 mins 1 % B Flow rate 0.8 ml / min Injection volume 2 ul

System C

Column Ymc ODS-AQ 2.0jA50mm 5um

Temperature 50 Degree Centigrade Mobile Phase A 0.0375% TFA in water (v/v)

Mobile Phase B 0.01875% TFA in acetonitrile (v/v)

Gradient - Initial 25% B

Time 0 mins 25% B

Time 0.5 mins 25% B Time 3.5 mins 100% B

Time 4.0 mins 25% B

Time 4.7 mins 25% B

Flow rate 0.8 ml / min

Injection volume 2 ul

For library preparative HPLC purification, five different columns were employed.

Column 1 Column 2 Column 3 Column 4 Column 5

Ymc ODS- Ymc ODS-AQ Ymc ODS-AQ Luna 5u C18 Sepax GP-C18 250*21.2mm 5um

AQ 150x20mm, 100x21.2mm, 100x21.2mm

75x30mm, 5um/0.1 % 5um/0.1 % TFA 0.1 %TFA

5um/0.1 % TFA TFA

Mobile Phase A: 0.075% TFA in water (v/v)

Mobile Phase B: 0.075% TFA in acetonitrile (v/v)

Example 1 Dicyclopropylmethyl-tθ^-methoxphenyO^.δ-dimethyl-ΘH-purin-δ-yll-amine

n BuOH (10 imL) was added to C,C-dicyclopropylmethylannine (2.50 g, 22.5 mMol) followed by triethylamine (3.31 ml_, 23.7 mMol) in one portion. To this stirred solution 6-Chloro-9-(4-methoxyphenyl)- 2,8-dimethyl-9H-purine (5.00 g, 17.3 mMol) was then added to give a pink mobile suspension. The reaction mixture was then heated to reflux for 16 hours under N₂ (g). The reaction mixture was cooled to room temperature then diluted with EtOAc (10 ml_) and washed with water (3 x 10 ml_). During the last aqueous wash, a solid precipitated out. EtOAc (10 ml_) was added with very little visible change. The organic layers were combined and concentrated in vacuo to 10 ml_ volume. This residue was then azeotroped with heptane (3 x 10 ml_) to give an off white solid. This was slurried in warm heptane (20 ml_) at 5O⁰C for 30 minutes. After cooling this was filtered and washed with fresh heptane (10 ml_) then dried at 5O⁰C under vacuum for 16 hours. The solid was recrystallised from hot EtOAc (8 ml_) to give the title compound as an off white solid (4.20 g, 67%).

¹H NMR (400MHz, CD₃OD) δ = 0.25-0.39 (m, 6H), 0.41-0.48 (m, 2H), 0.97-1.05 (m, 1 H), 2.27 (s, 6H), 3.62 (bs, 1 H), 3.78 (s, 3H), 7.03 (d, 2H), 7.22 (d, 2H). LCMS (System 1 ): 4.4 mins m/z (APCI) = 365 [MH+]

Example 2 Dicyclopropylmethyl-[9-(2-Chloro-4-fluorophenyl)-2,8-dimethyl-9H-purin-6-yl] -amine

6-Chloro-9-(2-chloro-4-fluorophenyl)-2,8-dimethyl-9H-purine (250 mg, 1.12 mMol), C,C- dicyclopropylmethylamine (442 mg, 5.62 mMol) and diisopropylethylamine (0.80 mL, 4.50 mMol) were dissolved in acetonitrile (3 ml_) and warmed under microwave conditions to 16O⁰C for 30 minutes. The reaction mixture was then partitioned between water (10 ml_) and EtOAc (10 ml_). The aqueous layer was then re-extracted with EtOAc (2 x 10 ml_). All organic fractions were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give a brown oil (610 mg). This was purified by column chromatography on ISCO system, 4Og silica cartridge, eluting with heptane to heptane:EtOAc 50:50 to give the title compound as an off white foam (118 mg, 27%). LRMS (System 2) 1.40 mins; m/z (APCI) = 386 [MH+]

Example 3 Dicyclopropylmethyl-EΘ-tS-fluoro^-methoxypheny^^.δ-dimethyl-ΘH-purin-θ-yll-amine

Diisopropylethylamine (1.17 ml_, 6.74 mMol) was added to a solution of 6-Chloro-9-(3-fluoro-4- methoxyphenyl)-2,8-dimethyl-9H-purine (3.37 mMol) and C,C-dicyclopropylmethylamine (1.50 g, 13.5 mMol) in anhydrous MeCN (15 ml_). The reaction mixture was then divided into three microwave vials and each was heated under microwave conditions at 15O⁰C for 1 hour. The reaction mixture from the 3 vials was combined and the solvent evaporated in vacuo to yield an oil. This was partitioned between saturated NaHCO₃ aqueous solution (50 ml_) and 1 M sodium hydroxide aqueous solution (10 ml_) and EtOAc (50 ml_). The aqueous was further washed with EtOAc (50 ml_). The combined organics were dried under anhydrous MgSO₄ (s) and the solvent evaporated in vacuo to give crude product as a yellow oil. Purification by column chromatography, twice, on the ISCO system, 8Og silica cartridge, eluting with heptane to heptane:EtOAc 50:50. Like fractions were combined to yield the title compound as a yellow sticky oil (0.657 g, 51 %). Material was 90% pure by NMR so it was then purified via a 1Og SCX cartridge conditioned with MeOH. The clean product was eluted with 25% NH₃/MeOH solution, and after concentrating in vacuo the title compound was afforded as a yellow solid (0.612 g, 48%) 1H NMR (400MHz, CDCI₃) δ = 0.40-0.56 (m, 8H), 1.00-1.09 (m, 2H), 2.44 (s, 3H), 2.49 (s, 3H), 3.49 (bs, 1 H), 3.97 (s, 3H), 5.59 (d, 1 H), 7.10-7.15 (m, 3H). LCMS (System 4) 2.71 mins; m/z (APCI) = 382[MH+]

Example 4 Dicyclopropylmethyl-tθ^-fluoro^-methoxyphenylJ^.δ-dimethyl-ΘH-purin-δ-yll-amine

Triethylamine (0.551 ml_, 3.95 mMol) was added to a solution of 6-Chloro-9-(2-fluoro-4-methoxyphenyl)- 2,8-dimethyl-9H-purine (885 mg, 2.88 mMol) and C,C-dicyclopropylmethylannine (417 mg, 3.75 mMol) in n-butanol (1.65 ml_). The reaction mixture was then heated to reflux for 12 hours under N₂ (g). The reaction mixture was then cooled to room temperature before removing the solvents in vacuo. The residue was partitioned between water (10 ml_) and EtOAc (3 x 10 ml_). The combined organics were dried over anhydrous MgSO₄ (s), filtered and the solvent evaporated in vacuo to give a brown gum (1.36 g). Purification by column chromatography on the ISCO system, 4Og silica cartridge, eluting with heptane to heptane:EtOAc 50:50 gave a yellow solid (573 mg). The solid was triturated with heptane, warmed and then allowed to cool for 5 minutes before filtering. The resultant solid was the dried to give the title compound as a white solid (453 mg, 41 %).

¹H NMR (400MHz, CD₃OD) δ = 0.34-0.63 (m, 8H), 1.12-1.22 (m, 2H), 2.39 (s, 3H), 2.43 (s, 3H), 3.76 (bs, 1 H), 3.95 (s, 3H), 6.99-7.06 (m, 2H), 7.43 (t, 1 H)

LCMS (System 4) 2.66 mins; m/z (APCI) = 382 [MH+].

Example 5 Dicyclopropylmethyl-[9-(4-difluoromethoxyphenyl)-2,8-dimethyl-9H-purin-6-yl] -amine

n Butanol (10 ml_) was added to C,C-dicyclopropylmethylamine (2.88 g, 25.9 mMol) followed by triethylamine (3.80 ml_, 27.3 mMol) in one portion. To this stirred solution 6-Chloro-9-(4- difluoromethoxyphenyl)-2,8-dimethyl-9H-purine (6.46 g, 19.9 mMol) was then added and the reaction mixture was then heated to reflux for 16 hours under N₂ (g). LCMS indicated incomplete reaction so further C,C-dicyclopropylmethylamine (1.11g, 9.95 mMol) was added and heating continued for another 6 hours. The reaction mixture was cooled to room temperature then diluted with EtOAc (60 ml_) and water (60 ml_). The aqueous layer was re-extracted with EtOAc (2 x 50 ml_). The combined organics were then evaporated in vacuo to give a brown gum. The residue was azeotroped with heptane (50 ml_) then triturated with cold heptane (20 ml_) to give crude product as a pale brown solid (6.3 g). This was combined with a second batch of material (8.8 g) for recrystallization. The solids were dissolved in EtOAc (320 ml_) and a spoon of charcoal was added. The reaction mixture was then filtered through a pad of celite and the filtrate was evaporated in vacuo, then azeotroped with heptane (50 ml_) to give a pale brown solid (12.6 g). This solid was dissolved in MTBE (14 ml_) at reflux. The reaction mixture was then slowly cooled to room temperatureover an hour before placing in a fridge for 16 hours. The crystals were collected by filtration and washed with cold MTBE (10 ml_). They were dried under high vacuum to give the title compound as a pale brown solid (10.4 g).

¹H NMR (400MHz, CD₃OD) δ = 0.39-0.53 (m, 6H), 0.55-0.62 (m, 2H), 1.12-1.20 (m, 2H), 2.42 (s, 3H), 2.44 (s, 3H), 3.77 (bs, 1 H), 7.00 (t, 1 H), 7.42 (d, 2H), 7.51 (d, 2H)

LCMS (System 1 ) 4.46 mins; m/z (APCI) = 400 [MH+]. Melting point: 101-102⁰C.

Example 6 Dicyclopropylmethyl-EΘ-tS-chloro^-methoxypheny^^.δ-dimethyl-ΘH-purin-θ-yll-amine

6-Chloro-9-(3-chloro-4-methoxyphenyl)-2,8-dimethyl-9H-purine (150 mg, 0.46 mMol) and C,C- dicyclopropylmethylamine (258 mg, 2.32 mMol) were dissolved in acetonitrile (3 mL) and warmed under microwave conditions to 16O⁰C for 30 minutes. The reaction mixture was then partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was then re-extracted with EtOAc (2 x 10 mL). All organic fractions were combined, dried over anhydrous Na₂SO₄ (s), filtered and evaporated in vacuo to give crude title compound as an orange gum (183 mg). This was purified by HPLC (singleton Method B, Retention time 3.00-3.05 min). LRMS(System 4) 2.85 mins; m/z (APCI) = 398 [MH+] Example 7

Dicyclopropylmethyl [9-(2-Chloro-4-difluoromethoxyphenyl)-2,8-dimethyl-9H-purin-6-yl]-amine

3-Chloro-4-[6-(dicyclopropylnnethylannino)-2,8-dinnethyl-purin-9-yl]-phenol (223 mg, 0.58 mMol) was dissolved in DMF (4 ml_). Water (1 ml_) was then added followed by chlorodifluoroacetic acid sodium salt (221 mg, 1.45 mMol) and cesium carbonate (284 mg, 0.87 mMol). The reaction mixture was then heated to 100⁰C for 16 hours under N₂(g). The reaction mixture was then partitioned between water (10 ml_) and EtOAc (10 ml_). The aqueous layer was then re-extracted with EtOAc (2 x 10 ml_). All organic fractions were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give crude title compound as a brown gum (300 mg). Purification by column chromatography on the ISCO system, 4Og silica cartridge, eluting with heptane to heptane:EtOAc 30:70 gave almost pure title compound as a yellow gum (30 mg, 12%). This material was further purified by HPLC (singleton Method B, Retention time 3.58-3.63min). LRMS (System 4 ) 3.04 mins; m/z (APCI) = 434 [MH+] Examples 8-31

Examples 8-31 were similarly prepared using library chemistry according to the method described above for example 2, starting from the appropriate aniline compound (0.5 mMol) and 2-methyl-4,6-dichloro-5- aminopyrimidine (0.5 mMol), with the final purification being by HPLC.

Example Ar HPLC LCMS column 8 1 (System A) 2.26 mins; m/z APCI = 378 [MH+]

(System A) 2.28 mins; m/z APCI = 348 [MH+]

(System A) 2.77 mins; m/z APCI = 378 [MH+]

(System A) 2.20 mins; m/z APCI = 373 [MH+]

(System A) 2.53 mins; m/z APCI = 359 [MH+]

1 (System A) 2.70 mins; m/z APCI = 394 [MH+]

1 (System A) 2.16 mins; m/z APCI = 389 [MH+]

(System A) 2.15 mins; m/z APCI = 352 [MH+]

(System A) 2.18 mins; m/z APCI = 370 [MH+]

(System A) 2.63 mins; m/z APCI = 352 [MH+]

(System A) 2.23 mins; m/z APCI = 366 [MH+]

(System A) 2.10 mins; m/z APCI = 334 [MH+]

(System A) 2.25 mins; m/z APCI = 393 [MH+]

(System C) 2.13 mins; m/z APCI = 368 [MH+]

(System C) 2.35 mins; m/z APCI = 402 [MH+]

(System C) 2.17 mins; m/z APCI = 418 [MH+]

(System A) 2.55 mins; m/z APCI = 377 [MH+]

(System A) 2.94 mins; m/z APCI = 427 [MH+]

26 ; m/z APCI = 414

Example 27

Dicyclopropylmethyl [9-(3,5-difluoro-4-methoxyphenyl)-2,8-dimethyl-9H-purin-6-yl]-amine

Dicyclopropylmethyl-^, 8-dimethyl-9H-purin-6-yl)-amine (0.05Og , 0.194 mmol), 4-bromo-2,6- difluoroanisole (0.087g , 0.388 mmol), Copper(l) Iodide (0.055g , 0.291 mmol), Cesium carbonate (0.158g , 0.485 mmol) and 1 ,10-Phenanthroline (0.070 g , 0.388 mmol) was dissolved in 2.0 ml of anhydrous DMF in a microwave vial with a septum cap. It was degassed alternatively with vacuum and nitrogen 3 times and then heated at 13O⁰C overnight in an oil bath. The crude was partitioned between 2 ml of water and 3 x 2 ml of DCM through a phase separating cartridge. Combined organics were dried under reduced pressure to yield a dark liquid which was purified by flash column chromatography in the ISCO system with 12g silica cartridge and a gradient of 0 to 40% EtOAc in heptane with sample loading in DCM. Fractions bearing product were combined to yield a transparent oil which was further purified by preparative HPLC method c. Fractions combined to yield the title compound as a solid (6.4mg, 8%).

¹H NMR (400MHz, CDCI₃) δ = 0.39-0.60 (m, 8H), 1.07 (m, 2H), 2.47 (s, 3H), 3.52 (s, 3H), 4.90 (s, 3H),

6.99 (d, 2H).

LCMS (System 4): 2.90 mins m/z (APCI) = 401 [MH+], m/z (ES) = 401 [MH+]

Example 28

Dicyclopropylmethyl [9-(4-chloro-2-methoxyphenyl)-2,8-dimethyl-9H-purin-6-yl]-amine

Dicyclopropylnnethyl-[9-(2-bronno-4-chlorophenyl)-2,8-dinnethyl-9H-purin-6-yl]-annine (100 mg, 0.224 mMol) was dissolved in MeOH (1 ml_) and transferred to a microwave vial. Copper I iodide (51.2 mg, 0.269 mMol) was then added followed by the addition of sodium methoxide (25% in MeOH solution) (1 mL). The mixture was warmed under microwave conditions to 12O⁰C for 30 mins. The reaction was quenched by addition of saturated ammonium chloride aqueous solution, then partitioned between EtOAc (10 ml) and water (10 ml). The aqueous layer was further extracted with EtOAc (2 x 10 ml_). The organic extracts were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give a brown gum (80 mg). Purification by column chromatography on the ISCO system, 4Og silica cartridge, eluting with EtOAc to EtOAc:MeOH:NH₃ 90:10:1 gave almost pure title compound as a pale brown gum (23 mg). This was further purified by singleton HPLC method c to yield title compound as a white solid (14 mg, 16%).

1H-NMR (400 MHz, CDCI₃) δ = 0.39-0.56 (m, 8H), 1.00-1.09 (m, 2H), 2.32 (s, 3H), 2.47 (s, 3H), 3.71- 3.79 (m, 1 H), 3.80 (s, 3H), 5.59 (bd, 1 H), 7.08 (d, 1 H), 7.1 1 (dd, 1 H), 7.22 (bd, 1 H). LCMS (System 4) 2.87 mins; m/z (APCI) = 398 [MH⁺]

Examples 29-33

Examples 29-33 were similarly prepared according to the method described above for example 4, starting from the appropriate aniline compound (0.3 mMol) and 2-methyl-4,6-dichloro-5-aminopyrimidine (0.3 mMol), with the final purification being by HPLC as singleton compounds.

Example Ar HPLC LCMS method 29 ns;

30 ns;

31 ns;

Example 34 3-Chloro-4-[6-(dicyclopropylmethyl-amino)-2,8-dimethyl-purin-9-yl]-benzonitrile

Dicyclopropylmethyl-(2,8-dimethyl-9H-purin-6-yl)-amine (0.03Og, 0.1 17mmol), 3-chloro-4- fluorobenzonitrile (0.022g , 0.140mmol) and Cs₂CO3 (0.114g , 0.351 mmol) was dissolved in 1 ml of anhydrous DMSO. The mixture was heated at 13O⁰C for 15 min in the microwave. The crude was partitioned between 10 ml of water and 2 x 10 ml of EtOAc. Combined organics were dried under MgSO₄ and the solvent evaporated to yield a yellow solid which was purified by flash column chromatography in the ISCO with 12g of silica and a gradient of 0 to 50% EtOAc in heptane. Fractions bearing product were combined to yield the title product as a white solid (18mg, 39%):

¹H NMR (400MHz, CDCI₃) δ = 0.37-0.59 (m, 8H), 1.0-1.10(m, 2H), 2.36 (s, 3H), 2.45 (s, 3H), 3.77(Br, 1 H), 5.69(br, 1 H), 7.52(d,1 H), 7.77(m, 1 H), 7.93(m, 1 H)

LCMS (System 2): 1.45 mins m/z (APCI) = 393 [MH+], m/z (ES) = 393 [MH+]

Example 35 Dicyclopropylmethyl-[9-(4-difluoromethoxy-2-fluoro-phenyl)-2,8-dimethyl-9H-purin-6-yl]-amine

4- [6 -( Dicyclopropylmethyl-amino)-2, 8- dimethyl -purin-9-yl]-3-fluoro-phenol (50mg, 0.136 mMol) was dissolved in dimethylformamide (2ml_). Water (0.1 ml_) was added followed by chlorodifluoroacetic acid sodium salt (51.8 mg, 0.340 mMol) and caesium carbonate (66.5 mg, 0.204 mMol). The reaction mixture was then heated to 100⁰C under N₂ for 18 hours. The reaction mixture was partitioned between 10 ml_ ethyl acetate and 10 ml_ brine. The organic layer was washed five times with 10 ml_ brine. The organic layer was then dried over magnesium sulphate, filtered and evaporated to give a brown gum (30mg, 53%). Purified by singleton prep HPLC method e, r.t. 3.60 min LCMS (System 4, acidic run): 2.97 mins m/z (APCI) = 418 [MH+]

Example 36 Dicyclopropylmethyl-[9-(4-difluoromethoxy-3-fluoro-phenyl)-2,8-dimethyl-9H-purin-6-yl] -amine

4- [6-( Dicyclopropylmethyl-annino)-2, 8- dimethyl -purin-9-yl]-2-fluoro-phenol (100mg, 0.272 m MoI) was dissolved in dimethylformannide (3mL). Water (0.2ml_) was added followed by chlorodifluoroacetic acid sodium salt (104 mg, 0.680 mMol) and caesium carbonate (133 mg, 0.408 mMol). The reaction mixture was then heated to 100⁰C under N₂ for 18 hours. The reaction mixture was partitioned between 10 mL ethyl acetate and 10 ml_ brine. The organic layer was washed five times with 10 ml_ brine. The organic was then dried over magnesium sulphate, filtered and evaporated to give a brown gum (45mg, 29%).

Purified by singleton prep HPLC method f

LCMS (System 4, acidic run): 2.94 mins m/z (APCI) = 418 [MH+] Example 37

2-(6-(dicyclopropylmethylamino)2,δ-dimethyl-9H-purin-9-yl)-5-(difluoromethoxy)benzonitrile

The 9-(2-Bromo 4-(difluoromethoxy)phenyl)-N-(dicyclopropylmethyl)-2,8-dimethyl-9H-purine-6-amine (30 mg, 0.0627 mMol), CuCN (>5 eq., 0.06 g) in DMF (3 mL) and heated in a microwave at 190 ⁰C for 1 hour 30 minutes. The reaction was cooled to RT and quenched with cone. NH₃ solution (5 mL), extracted with EtOAc (50 mL), washed with brine (20 mL), dried over Na₂SO₄ and concentrated which gave the title compound as a brown gum (30 mg, 100 %). Purified by singleton prep HPLC method d, RT 3.36 min LCMS (System 5): 2.50 mins, m/z = 425.20 [M+H] Rt 3.36min

Example 38 Λ/-(Dicyclopropylmethyl)-9-(4-(difluoromethoxy)-3-methoxyphenyl)-2,8-dimethyl-9H-purine

Acetonitrile (2.5 ml_) was added to a mixture 6-chloro-9-(4-(difluoromethoxy)-3-methoxyphenyl)-2,8- dimethyl-9/-/-purine (0.060 g, 0.17 mMol). To this solution was added C,C-dicyclopropylmethylannine hydrochloride (0.059 g, 0.34 mMol) and triethylamine (0.139 ml_, 1.00 mMol). The reaction mixture was heated in a microwave reactor at 15O⁰C for 5 hours. LCMS analysis indicated that starting material was still present so triethylamine (0.139 ml_, 1.00 mMol) was added to the reaction mixture and it was heated in a microwave reactor at 15O⁰C for an additional 5 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to give the title compound as a brown solid (0.025 g, 34%).

¹H NMR (300MHz, CDCI₃) δ = 0.38-0.49 (m, 10H), 0.96-1.07 (m, 1 H), 2.42 (s, 3H), 2.46 (s, 3H), 3.86 (s, 3H), 5.60 (d, 1 H), 6.58 (t, 1 H), 6.84 (d, 1 H), 6.95 (s, 1 H), 7.28 (d, 1 H)

LCMS (System 5): 2.6 mins m/z = 430 [MH+]

Example 39 Dicyclopropylmethyl-[9-(2,6-difluoro-4-methoxyphenyl)-2,8-dimethyl-9H-purin-6-yl] -amine

To stirring 4-(6-(dicyclopropylmethylamino)-2,8-dimethyl-9H-purin-9-yl)-3,5-difluorophenol (0.15 g, 0.4 mMol) in acetonitrile (10 mL) was added potassium carbonate (0.07 g, 0.5 mMol) followed by iodomethane (0.05 mL, 0.5 mMol) in one portion. The reaction mixture was then heated at 7O⁰C for 16 hours. The reaction mixture was cooled then the solvent removed under rotary evaporation. The residue was diluted with EtOAc (10 ml_) and washed with 1 M NaOH (aq, 10 ml_), water (10 ml_), then brine (10 ml_). The organic layer was evaporated under rotary evaporation to give the title compound (0.15 g,

67%).

Purified by singleton prep HPLC method d, r,t, 3.55 min

LCMS (System 5): 2.57 mins m/z (ES+) = 400 [MH+]

Example 40 Λ/^DicyclopropylmethyO-Θ^S^difluoromethoxyJ^-methoxyphenylJ^.δ-dimethyl-ΘH-purine

Acetonitrile (2.5 mL) was added to the mixture from preparation 48 (0.060 g). To this solution was added CC-dicyclopropylmethylamine hydrochloride (0.059 g, 0.34 mMol) and triethylamine (0.139 mL, 1.00 mMol). The reaction mixture was heated in a microwave reactor at 15O⁰C for 5 hours. LCMS analysis indicated that starting material was still present so triethylamine (0.139 mL, 1.00 mMol) was added to the reaction mixture and it was heated in a microwave reactor at 15O⁰C for an additional 5 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to give the title compound as a brown solid (0.025 g, 34%).

¹H NMR (300MHz, CDCI₃) δ = 0.32-0.58 (m, 10H), 0.98-1.08 (m, 1 H), 2.42 (s, 3H), 2.46 (s, 3H), 3.97 (s, 3H), 5.63 (d, 1 H), 6.61 (t, 1 H), 7.10 (d, 1 H), 7.18-7.27 (m, 2H) LCMS (System 5): 2.5 mins m/z = 430 [MH+]

Example 41 5-(6-(Dicyclopropylmethylamino)-2,8-dimethyl-9H-purin-9-yl)-2-(difluoromethoxy)benzonitrile

9-(3-Bromo-4-(difluoromethoxy)phenyl)-N-(dicyclopropylmethyl)-2,8-dimethyl-9H-purin-6-amine (0.11g, 0.23 mMol) and copper cyanide (0.1 Og, 1.16 mMol) in DMF (2 ml_) were heated in the microwave at 190⁰C for 3 hours. The reaction was quenched with 0.880 NH₃ (0.5 ml.) then water (5 ml.) and EtOAc (5 imL) were added. The phases were separated and the organic phase was washed with brine (5 ml_), dried (MgSO₄), filtered and the solvent removed in vacuo to give a brown oil. This was purified by column chromatography (49:1 CH₂CI₂: MeOH) to give the crude title compound as a brown oil at 30% purity. Purified by singleton prep HPLC method e, r.t. 3.45 min

LCMS : (System 5) 2.52 mins (30 %), m/z 425.13 [M+H]⁺

Example 42 Λ/-(Dicyclopropylmethyl)-9-(4-(difluoromethoxy)-2-methoxyphenyl)-2,8-dimethyl-9H-purine

Acetonitrile (10.0 mL) was added to a mixture 6-chloro-9-(4-(difluoromethoxy)-2-methoxyphenyl)-2,8- dimethyl-9/-/-purine (1.07 g, 3.03 mMol). To this solution was added C, C- dicyclopropylmethylaminehydrochloride (1.06 g, 6.05 mMol) and triethylamine (2.52 mL, 18.16 mMol). The reaction mixture was heated in a microwave reactor at 15O⁰C for 1 hour. Hot EtOAc was added to the reaction mixture, followed by hexane. The reaction mixture was cooled to room temperature and the crystals formed were collected by filtration to give the title compound as a brown solid (0.46 g, 36%). ¹H NMR (300MHz, CDCI₃) δ = 0.32-0.60 (m, 8H), 0.98-1.12 (m, 2H), 2.31 (s, 3H), 2.47 (s, 3H), 3.77 (s, 3H), 5.66 (d, 1 H), 6.59 (t, 1 H), 6.78-6.92 (m, 2H), 7.27 (d, 1 H)

LCMS (System 5): 2.6 mins m/z = 430 [MH+] Preparation 1 6-Chloro-N*4*-(4-methoxyphenyl)-2-methylpyrimidine-4,5-diamine

4,6-dichloro-2-methyl-pyrimidin-5-ylamine (985.3 g, 5.53 MoI) was added with stirring to a 2OL reactor charged with EtOH (4.0 L) over 3 minutes to give complete solution. p-Anisidine (718.0 g, 5.83 MoI) was then added with stirring over 3 minutes. A dark brown solution was observed and addition of both reagents gave an exotherm of 13⁰C. EtOH (1 L) was then added followed by a premixed solution of c.HCI (0.5 L) in EtOH (2 L) at a steady rate over 40 minutes. A slight exotherm up to approx 2O⁰C was noted. The solution was then warmed to 8O⁰C and held at that temperature for 3.5 hours during which a grey precipitate appeared. Heating was continued for a further 2 hours then the temperature was reduced to 49⁰C, and stirring was continued for 19 hours. The reaction mixture was allowed to cool to 3O⁰C, before draining out of 2OL reactor. The reaction mixture was filtered to collect a beige precipitate. Washed with EtOH (2.5 L), the MTBE (2.5 L) and sucked dry under N₂(g) for 22 hours. The filter cake was then dried under vacuum at 5O⁰C for 60 hours, to yield title compound, as the hydrochloride salt, as a beige solid (1.465 Kg, 88%). 1H NMR (400MHz, DMSO-d6) δ = 2.27 (s, 3H), 3.71 (s, 3H), 6.90 (d, 2H), 7.58 (d, 2H), 9.10 (bs, 1 H). LCMS (System 4): 2.4 mins m/z (APCI) 265 [MH⁺]

Preparation 2 6-Chloro-9-(4-methoxyphenyl)-2,δ-dimethyl-9H-purine

θ-Chloro-NM^^-methoxyphenyl^-methylpyrimidine^S-diamine hydrochloride (1.50 Kg, 4.98 MoI) was added with stirring over 10 minutes, to a solution of triethylamine (560 ml_) in MeCN (5 L) in a 2OL reactor under N₂(g). MeCN (2.5 L) was then added followed by trimethyl orthoacetate (1.16 Kg, 9.64 MoI) over 15 minutes. A dark brown solution resulted which was heated at 74⁰C (reaction temperature) for 21 hours. The reaction mixture was cooled to 35⁰C and triethylamaine (233 mL) was added. The solution was drained into a solvent flint without stirring. Acetonitrile (2.5 L) was added to the remaining solid in the reactor and after stirring this was drained again. The reaction mixture was then concentrated in vacuo to a low volume brown slurry. EtOAc / H₂O (1 L:1 L) was then added and the solution was stirred for an hour before being siphoned into a 3OL extractor. The flask was washed with a further 1.5 L EtOAc and 2.5 L H₂O, again this was added to the extractor followed by EtOAc / H₂O (6 L: 1 L). The aqueous slurry was run off and the organic layer was washed with fresh water (2 L). The aqueous slurry was again run off until only the clear dark brown organic layer remained. This was run off then concentrated in vacuo. The aqueous slurries were sequentially re-extracted with EtOAc (5 L). These organic extracts were combined with the previous organic slurries and all were concentrated to a slurry of approximately 2 L volume, before leaving to stand overnight. The slurry was azeotroped with heptane (2 L then 3 x 1 L) keeping the total slurry volume between 3-4 L. It was allowed to cool briefly then was filtered and washed with heptane (2.5 L). The solid was then dried at 5O⁰C under vacuum with a N₂ bleed for 5 days to yield the title compound, as a 85:15 ratio of chloropurine:methoxy adduct, as an off white solid (1.375 Kg, 85% product). 1H NMR (400MHz, CDCI₃) δ = 2.52 (s, 3H), 3.71 (s, 3H), 3.89 (s, 3H), 7.08 (d, 2H), 7.27 (d, 2H) LCMS (System 4): 2.6 mins m/z (ESI) = 289 [MH+]

Preparation 3 6-Chloro-N*4*-(2-chloro-4-fluorophenyl)-2-methylpyrimidine-4,5-diamine

2-Chloro-4-fluoroaniline (327 mg, 2.25 mMol), 2-methyl-4,6-dichloro-5-aminopyrimidine (400 mg, 2.25 mMol), anhydrous 2-methoxyethanol (8 mL) and 2M aqueous hydrogen chloride solution (2.25 mL) were heated under microwave conditions at 16O⁰C for an hour. The solvents were then removed in vacuo and the residue was partitioned between saturated aqueous NaHCO₃ solution (10 mL) and EtOAc (10 mL).

The aqueous layer was then re-extracted with EtOAc (2 x 10 mL). All organic fractions were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to yield crude title compound as a brown solid (625 mg, 100%). LRMS (System4 ) 2.95 mins; m/z (APCI) = 287 [MH+]

Preparation 4 6-Chloro-9-(2-chloro-4-fluorophenyl)-2,8-dimethyl-9H-purine

6-Chloro-N*4*-(2-chloro-4-fluorophenyl)-2-nnethylpyrinnidine-4,5-diannine (645 mg, 2.25 imMol) and pTSOH (6 mg, 0.03 imMol) were dissolved in EtOH (8 ml_). To this triethylorthoacetate (8 ml_) was added and the solution was warmed to reflux under N₂ (g) for 16 hours. The reaction mixture was then cooled and evaporated in vacuo to dryness. The residue was dissolved in CH₂CI₂ (8 ml_) and TFA (0.173 ml_, 2.25 mMol) was added. The reaction mixture was then stirred at room temperature, under N₂ (g) for 6 hours. Saturated aqueous NaHCO₃ solution (10 ml_) and CH₂CI₂ (10 ml_) were then added. The layers were separated and the aqueous was re-extracted with CH₂CI₂ (2 x 10 ml_). The organic fractions were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give a brown gum (1.4 g). Purification by chromatography on ISCO system, 4Og silica cartridge, eluting with heptane to heptane:EtOAc 50:50 gave the title compound as a yellow solid (351 mg, 50%). LRMS (System 2) 1.33 mins; m/z (APCI) = 31 1 [MH+]

Preparation 5 6-Chloro-N*4*-(3-fluoro-4-methoxyphenyl)-2-methylpyrimidine-4,5-diamine

2-Methyl-4,6-dichloro-5-aminopyrimidine (0.60 g, 3.37 mMol) and 3-fluoro-4-methoxyaniline (0.467 g, 3.37 mMol) were dissolved in anhydrous methoxyethanol (12 mL). 2M Aqueous hydrogen chloride solution (3.37 mL, 6.74 mMol) was added and the mixture was heated at 12O⁰C for 16 hours. The reaction mixture was cooled then neutralised with sat. NaHCO₃ aqueous solution (50 mL) and extracted with EtOAc (3 x 50 ml_). The combined organics were dried under anhydrous MgSO₄ (s), filtered and the solvent evaporated in vacuo to give a yellow oil. This was used in the next step without further purification.

LCMS (System4) 2.58 mins; m/z (APCI) = 283 [MH⁺]

Preparation 6 6-Chloro-9-(3-fluoro-4-methoxyphenyl)-2,8-dimethyl-9H-purine

Triethyl orthoacetate (15 ml_, 82.2 mMol) was added to a room temperature solution of 6-Chloro-N*4*-(3- fluoro-4-methoxyphenyl)-2-methylpyrimidine-4,5-diamine (953 mg, 3.37 mMol) in EtOH (15 ml_). pTSOH (9.7 mg, 0.05 mMol) was then added and the resultant solution was heated at 9O⁰C for 5 hours. Some precipitate was observed in the reaction mixture. The reaction volume was reduced in vacuo and the residue partitioned between saturated NaHCO₃ aqueous solution (50 ml_) and EtOAc (3 x 50 ml_). The combined organics were dried under anhydrous MgSO₄ (s), filtered and the solvent evaporated in vacuo to give a solid (>100%). This was used without further purification. LCMS (System2) 1.30 min; m/z (APCI) = 307 [MH⁺]

Preparation 7 6-Chloro-N*4*-(2-fluoro-4-methoxyphenyl)-2-methylpyrimidine-4,5-diamine

2-Methyl-4,6-dichloro-5-aminopyrimidine (0.50 g, 2.81 mMol) and 2-fluoro-4-methoxyaniline (0.416 g, 3.00 mMol) were dissolved in ethanol (10 mL). 2M Aqueous hydrogen chloride solution (1.5 mL, 3.00 mMol) was added and the mixture was heated at 8O⁰C for 16 hours under N₂ (g).The solvent was evaporated in vacuo, and the reaction mixture was then dissolved in EtOAc (10 mL) and basified to pH= 8-9 with saturated NaHCO₃ aqueous solution. The layers were then separated and the organic layer was dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give crude title compound as a brown solid (772 mg, 97%).

LCMS (System 2) 1.23 mins; m/z (APCI) = 283 [MH+]

Preparation 8 6-Chloro-9-(2-fluoro-4-methoxyphenyl)-2,8-dimethyl-9H-purine

Triethyl orthoacetate (0.58 ml_, 0.64 mMol) was added to a room temperature solution of 6-Chloro-N*4*- (2-fluoro-4-methoxyphenyl)-2-methylpyrimidine-4,5-diamine (772 mg, 2.73 mMol) in toluene (10 ml_). pTSOH (5.7 mg, 0.03 mMol) was then added and the resultant solution was heated at 1 1O⁰C for 16 hours under N₂ (g). The reaction mixture was cooled then the volume was reduced in vacuo and the residue partitioned between saturated NaHCO₃ aqueous solution (10 ml_) and EtOAc (3 x 10 ml_). The combined organics were dried over anhydrous MgSO₄ (s), filtered and the solvent evaporated in vacuo to give crude title compound, as a 60:40 ratio of chloropurine:methoxy adduct, as a dark gum (885 mg). This was used without further purification.

LCMS (System4) 2.70 mins; m/z (APCI) = 307 [MH⁺]

Preparation 9 6-Chloro-N*4*-(4-difluoromethoxyphenyl)-2-methylpyrimidine-4,5-diamine

4,6-dichloro-2-methyl-pyrimidin-5-ylamine (20.0 g, 110 MoI) was added with stirring to EtOH (80 mL) over 3 minutes to give complete solution. 4-Difluoromethyoxyaniline (18.8 g, 118 MoI) was then added with stirring over 3 minutes. A dark brown solution was observed. EtOH (20 mL) was then added followed by a premixed solution of c.HCI (10 mL) in EtOH (40 mL) at a steady rate over 20 minutes. A slight exotherm up to approx 2O⁰C was noted. The solution was then warmed to 85⁰C and held at that temperature for 4 hours. The reaction mixture was then cooled to room temperature, and a beige solid precipitated. This reaction mixture was filtered then washed with EtOH (100 ml_) followed by MTBE (3OmL) to remove EtOH traces. The resultant solid was dried in vacuo over the weekend to give the title compound, as the hydrochloride salt, as a beige solid (17.2 g, 45%) 1H NMR (400MHz, CD₃OD) δ = 2.55 (s, 3H), 6.89 (t, 1 H), 7.27 (d, 2H), 7.75 (d, 2H) LCMS (System 4) 3.07 mins; m/z (APCI) = 301 [MH+]

Preparation 10

6-Chloro-9-(4-difluoromethoxyphenyl)-2 ,8-dimethyl-9H-purine

6-Chloro-N*4*-(4-difluoromethoxyphenyl)-2-methylpyrimidine-4,5-diamine hydrochloride (17.2 g, 51.0 mMol) was added with stirring over 5 minutes, to a solution of triethylamine (5.74 mL, 41.2 mMol) in acetonitrile (58 mL) under N₂(g). A slight suspension was observed after the addition. Acetonitrile (28 mL) was then added followed by trimethyl orthoacetate (13.3 mL, 98.7 mMol) over 5 minutes. A dark brown solution resulted which was heated at 74⁰C (reaction temperature) for 21 hours. The reaction mixture was cooled to room temperature and triethylamine (2.38 mL, 0.35 mMol) was added. The reaction mixture was then evaporated in vacuo to dryness. The residue was dissolved in EtOAc (35 mL) and water (35 mL) and stirred vigourously for an hour. EtOAc (200 mL) and water (150 mL) were then added and the layers were separated. The organic layer was then evaporated in vacuo to give a dark gum. This residue was azeotroped with heptane ( 5 x 100 mL) then allowed to cool briefly. The reaction mixture was then triturated with diethyl ether ( 4 x 100 mL) and filtered to give the title compound as a pink solid (6.46 g, 39%). The filtrate was also evaporated in vacuo to give the title compound, as a 25:75 ratio of chloropurine:methoxy adduct, as a brown solid (9.28 g).

¹H NMR (400MHz, CD₃OD) δ = 2.58 (s, 3H), 2.67 (s, 3H), 7.02 (t, 1 H), 7.45 (d, 2H), 7.61 (d, 2H) LCMS (System 2) 1.36 mins; m/z (APCI) = 325 [MH+]

Preparation 11 6-Chloro-N*4*-(3-chloro-4-methoxyphenyl)-2-methylpyrimidine-4,5-diamine

3-Chloro-4-methoxyaniline (177 mg, 1.12 mMol), 2-nnethyl-4,6-dichloro-5-anninopyrinnidine (200 mg, 1.12 mMol), anhydrous 2-methoxyethanol (4 mL) and 2M aqueous hydrogen chloride solution (1.12 ml_) were heated under microwave conditions at 16O⁰C for an hour. The solvents were then removed in vacuo and the residue was partitioned between saturated aqueous NaHCO₃ solution (10 mL) and EtOAc (10 mL). The aqueous layer was then re-extracted with EtOAc (2 x 10 mL). All organic fractions were combined, washed with brine (10 mL) then dried over anhydrous Na₂SO₄ (S), filtered and evaporated in vacuo to yield crude title compound as a brown gum (350 mg, 100%). LRMS (System 4) 2.78 mins; m/z (APCI) = 299 [MH+]

Preparation 12 δ-Chloro-θ-β-chloro^-methoxyphenyl^.δ^Nmethyl-ΘH-purine

Triethyl orthoacetate (8.0 mL) was added to a room temperature solution of 6-Chloro-N*4*-(3-chloro-4- methoxyphenyl)-2-methylpyrimidine-4,5-diamine (350 mg, 1.17 mMol) in EtOH (8 mL). pTSOH (3 mg, 0.02 mMol) was then added and the resultant solution was heated at 8O⁰C for 16 hours under N₂ (g). The reaction mixture was cooled then the volume was reduced in vacuo The residue was then dissolved in CH₂CI₂ (5 mL) and TFA (0.092 mL, 1.19 mMol) was added. The reaction mixture was stirred at room temperature for 6 hours. Saturated NaHCO₃ aqueous solution (10 mL) was added and the layers separated. The organic layer was dried over anhydrous Na₂SO₄ (s), filtered and the solvent evaporated in vacuo to give crude title compound as a dark gum (400 mg, 100%). This was used without further purification. LCMS (System4)1.38 mins; m/z (APCI) = 323 [MH⁺]

Preparation 13 4-(5-Amino-6-chloro-2-methylpyrimidin-4-ylamino)-3-chlorophenol

2-Chloro-4-hydroxyaniline hydrochloride (303 mg, 1.68 mMol), 2-methyl-4,6-dichloro-5-aminopyrimidine (300 mg, 1.68 mMol), anhydrous 2-methoxyethanol (4 ml_) and 2M aqueous hydrogen chloride solution (1.68 ml_) were heated under microwave conditions at 16O⁰C for an hour. The solvents were then removed in vacuo and the residue was adjusted to pH = 7. The reaction mixture was then partitioned between water (10 ml_) and EtOAc (10 ml_). The aqueous layer was then re-extracted with EtOAc (2 x 10 ml_). All organic fractions were combined then dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to yield crude title compound as an orange solid (329 mg, 68%). LRMS (System 4) 2.24 mins; m/z (ESI) = 285 [MH+]

Preparation 14 3-Chloro-4-(6-chloro-2,8-dimethyl-purin-9-yl) -phenol

Triethyl orthoacetate (8.0 ml_) was added to a room temperature solution of 4-(5-Amino-6-chloro-2- methylpyrimidin-4-ylamino)-3-chlorophenol (329 mg, 1.15 mMol) in EtOH (8 ml_). pTSOH (3 mg, 0.02 mMol) was then added and the resultant solution was heated at 8O⁰C for 16 hours under N₂ (g). The reaction mixture was cooled then the volume was reduced in vacuo The residue was then partitioned between CH₂CI₂ (5 ml_) and saturated NaHCO₃ aqueous solution (10 ml_). The organic layer was washed with water (10 ml_) then dried over anhydrous MgSO₄ (s), filtered and the solvent evaporated in vacuo to give crude title compound. Purification by column chromatography on the ISCO system, 4Og silica cartridge, eluting with heptane to heptane:EtOAc 50:50 gave a yellow solid (133 mg, 37.3%). 1H NMR (400MHz, CDCI₃) δ = 2.42 (s, 3H), 2.80 (s, 3H), 6.78 (dd, 1 H), 6.83 (s, 1 H) 7.17 (d,1 H), 9.98 (bs, 1 H). LCMS (System 4) 2.50 mins; m/z (APCI) = 309 [MH⁺]

Preparation 15 3-Chloro-4-[6-(dicyclopropylmethylamino)-2,8-dimethyl-purin-9-yl] -phenol

6-Chloro-4-(6-chloro-2,8-dimethyl-purin-9-yl)-phenol (133 mg, 0.43 mMol) and C, C- dicyclopropylmethylamine (239 mg, 2.19 mMol) were dissolved in acetonitrile (3 ml_) and warmed under microwave conditions to 16O⁰C for 30 minutes. The reaction mixture was then partitioned between water (10 ml_) and EtOAc (10 ml_). The aqueous layer was then re-extracted with EtOAc (2 x 10 ml_). All organic fractions were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give crude title compound as an orange gum (223mg, 135%). This was taken on without purification to the next step. LRMS (System 4 ) 2.59 mins; m/z (APCI) = 384 [MH+]

Preparation 16 6-Chloro-N*4*-(2-bromo-4-chlorophenyl)-2-methylpyrimidine-4,5-diamine

2-Bromo-4-chloroaniline (2.45 g, 11.9 mMol) was added to a stirred solution of 2-methyl-4,6-dichloro-5- aminopyrimidine (2.11 g, 11.9 mMol) in EtOH (1 1 ml_). A solution of c.HCI (1.06 mL) in EtOH (4 ml.) was then added drop-wise over 20 minutes. A slight exotherm was noted on addition.The reaction mixture was then heated at 85⁰C for 16 hours. Upon cooling to room temperature a solid precipitated. This was filtered and washed with EtOH (25 mL) then MTBE (25 mL) before drying under high vacuum. This gave title compound as a white solid as the hydrochloride salt (2.5 g, 55%).

¹H NMR (400MHz, CD₃OD) δ = 2.40(s, 3H), 7.55 (dd, 1 H), 7.53 (d, 1 H), 7.79 (s, 1 H)

LRMS (System2 ) 1.56 mins; m/z (APCI) = 349 [MH+]

Preparation 17 6-Chloro-9-(2-bromo-4-chlorophenyl)-2,8-dimethyl-9H-purine

6-Chloro-N*4*-(2-bronno-4-chlorophenyl)-2-nnethylpyrinnidine-4,5-diannine hydrochloride (2.50 g, 6.50 mMol) was added to a solution of triethylamine (0.73 ml_, 6.5 mmol) in MeCN (1 1 ml_) To this triethylorthoacetate (1.7 ml_, 12.6 mMol) was added and the solution was warmed to 74⁰C under N₂ (g) for 16 hours. Reaction was incomplete so triethylamine (0.30 ml_, 2.18 mMol) was added to quench any excess reagents prior to evaporating in vacuo to dryness. The residue was dissolved in EtOAc (20 ml_) / water (20 ml_) and the solution was stirred vigorously for an hour at room temperature. Water (50 ml_) and EtOAc (50 ml_) were then added. The organic fraction was dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give the title compound, as a 60:40 ratio of chloropurine:methoxy adduct, as a pale yellow sol id (2.5 g, 95%). This was taken on without purification to the next step. LRMS (System 4) 3.79 mins; m/z (APCI) = 405 [MH+]

Preparation 18 Dicyclopropylmethyl-[9-(2-bromo-4-chlorophenyl)-2,8-dimethyl-9H-purin-6-yl] -amine

CC-dicyclopropylmethylamine (894 mg, 8.04 mMol) and triethylamine (1.18 ml_, 8.50 mMol) were added to a solution of crude 6-chloro-9-(2-bromo-4-chlorophenyl)-2,8-dimethyl-9H-purine (2.5 g, 6.19 mMol) in n-butanol (5 ml_). The reaction mixture was then warmed to reflux under N₂ (g) for 16 hours. The reaction mixture was cooled then evaporated in vacuo to dryness. Water (30 ml_) and EtOAc (30 ml_) were added and the layers were separated. The aqueous layer was then re-extracted with EtOAc (2 x 20 ml_). All organic fractions were combined, dried over anhydrous MgSO₄ (s), filtered and evaporated in vacuo to give a pale brown solid. This was triturated with heptane, filtered and evaporated to give the title compound as a pale brown solid (2.1 g, 78%). ¹H NMR (400 MHz, CD₃OD) δ = 0.35-0.60 (m, 8H), 1.08-1.17 (m, 2H), 1.34-1.43 (m, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.71 (bs, 1 H), 7.53 (d, 1 H), 7.64 (dd, 1 H), 7.96 (d, 1 H). LRMS (System 4) 3.1 1 mins; m/z (APCI) = 447 [MH+]

Preparation 19 6-Chloro-2-methyl-pyrimidine-4,5-diamine

2-methyl-4,6-dichloro-5-aminopyrinnidine (2. g , 11.235 mmol) was suspended in 20 ml of 37% aqueous ammonia. The mixture was shared between 4 high pressure vials and they were heated at 100°C for 10 min. The temperature was then reduced to 7O⁰C and maintained overnight. LCMS indicates 80% conversion by TIC. Upon cooling the precipitated product was filtered and washed with water to yield the title product as a yellow solid (1.125g, 63%): LCMS (System 2): 0.30 mins (2 min run) m/z (APCI) = 159 [MH+], m/z (ES) = 159 [MH+]

Preparation 20

1-(6-Chloro-2,8-dimethyl-purin-9-yl)-ethanone

6-Chloro-2-methyl-pyrimidine-4,5-diamine (1.03 g, 6.495 mmol) was dissolved in 20 ml of acetic anhydride and 20 ml of triethylorthoacetate. It was stirred at room temperature for 20 min and then heated to 100°C under nitrogen and maintained at 100°C for 3h. Temperature was then increased to

11O⁰C for another 1 h.

The solvent was evaporated under reduced pressure and the residue taken with 20 ml NaOH (1 M aq) and heated at 9O⁰C for 5 min. It was then extracted with 3 x 20 ml of EtOAc. The aqueous was brought to pH 5 with acetic acid and it was further extracted with 2 x 30 ml of EtOAc. Combined organics were dried under MgSO₄ and the solvent evaporated under reduced pressure to yield a yellow solid (1.3g) which was purified by flash column chromatography in the ISCO system with 8Og of silica anda gradient of 0 to

20% EtOAc in heptane.

Fractions from the first peak eluted were combined to yield 1-(6-Chloro-2,8-dimethyl-purin-9-yl)-ethanone as a white solid (419mg, 29%) 1H NMR (400MHz, CDCI₃) δ = 3.04(s, 3H), 2.87(s, 3H), 2.77(s, 3H)

LCMS (System 4): 2.38 mins m/z (ES) = 225 [MH+], 183 [M-41(Ac loss)] Preparation 21 Dicyclopropylmethyl-(2,8-dimethyl-9H-purin-6-yl) -amine

1-(6-Chloro-2,8-dimethyl-purin-9-yl)-ethanone (0.30Og ,1.335mnnol) was dissolved in 3.0 ml of anhydrous DMSO. C,C-dicyclopropylmethylamine (0.742g , 6.68 mmol), CsF (0.243g , 1.60 mmol) and DIPEA (0.465 ml , 2.67 mmol) were added. The mixture was heated at 15O⁰C in the microwave for 3h. The reaction mixture was partitioned between 30 ml of water and 3 x 30 ml of EtOAc. Combined organics were dried under MgSO₄ and the solvent evaporated under reduced pressure to yield an orange solid which was triturated in MeCN to yield the title product as an off white solid (504mg, >100%):

¹H NMR (400MHz, CDCI₃) δ = 0.39-0.58 (m, 8H), 1.06 (m, 2H), 2.62 (s, 3H), 2.65 (s, 3H), 3.76 (br, 1 H).

LCMS (System 4): 2.03 mins

LCMS (System 2): 0.89min; m/z (APCI) = 258 [MH+], m/z (ES) = 258 [MH+]

Preparation 22

4-amino-3-fluoro -phenol

A solution of 3-fluoro-4-nitro-phenol (400 mg, 2.55 mMol) and ethanol (6 mL) was treated with 10% Pd/C (42.6 mg). The reaction mixture was hydrogenated for 3 hours at 40 psi at room temperature. The reaction mixture was filtered through a pad of Arbocel ® with ethanol and then evaporated to dryness to give a dark solid (290mg, 90%).

¹H NMR (400MHz, CD₃OD) δ = 6.32-6.41(dd, 2H), 6.58-6.63 (m, 1 H).

GC/MS: 1.9 mins m/z (Cl) = 128 [MH+]

GC/MS conditions: OVEN

Initial temp: 50 C Maximum temp: 320 C Initial time: 0.5 mi Rate: 45 C/min Carrier gas: He

COLUMN

Zebron™ ZB-5™

Column Length(m)= 15.00 Column Diameter(um)=250.00

Film Thickness(um)= 0.25

PRESSURE

Time: 4.1

Rate (kPa/min) 0.8 Final pressure: 2.0 kPa

INJECTOR

Injection volume 2 uL

MS

Function type: TOF MS Mass range: 50 to 800 lonisation mode: Cl and El

Preparation 23 4-(5-amino-6-chloro-2-methyl-pyrimidin-4-ylamino)-3-fluoro -phenol

A 10ml flask was charged with EtOH (3ml_). 2-methyl-4,6-dichloro-5-aminopyrimidine was added (140mg, 1.89 mMol) followed by 4-amino-3-fluoro-phenol (100mg, 1.89 mMol) and HCI (2M aq, 0.787ml_, 3.78 mMol). The reaction mixture was heated at 85⁰C under N₂ for 6 hours. The reaction mixture was evaporated, partitioned between 10 ml sodium bicarbonate solution and 10 ml ethyl acetate, the aqueous was extracted again twice with 10 ml ethyl acetate, the organics were combined, dried over magnesium sulphate, filtered and evaporated to give a purple gum (416 mg, 82%).

LCMS (System 4, acidic run): 2.02 mins m/z (APCI) = 269 [MH+]

Preparation 24 4-(6-chloro-2, δ-dimethyl-purin-9-yl)-3-fluoro-phenol

A 25 mL flask (under flow N₂) was charged with MeCN (5ml_) and then Et₃N (0.174ml_, 0.807 mMol). 4- (5-amino-6-chloro-2-nnethyl-pyrinnidin-4-ylannino)-3-fluoro-phenol (416 mg, 1.55 mMol) was added followed by trimethylorthoacetate (0.406 mL, 3 mMol). The reaction mixture was heated at 74⁰C under N₂ for 18 hours. Et₃N (72uL, 0.519 mMol) was finally added and the reaction mixture was stirred at room temperature for one hour under N₂. The reaction mixture was evaporated, partitioned between 10 mL ethyl acetate and 10 mL water. The aqueous was extracted twice with 10 mL ethyl acetate. The organics were combined, dried over magnesium sulphate, filtered and evaporated to give a pink gum (453 mg, 96%) containing a mixture of desired product and imidoester intermediate. LCMS (System 4, acidic run): 2.34 mins m/z (APCI) = 293 [MH+]

LCMS (System 4, acidic run): 2.66 mins m/z (APCI) = 325 [imidoester intermediate]

Preparation 25

4- [6-( Dicyclopropylmethyl-amino)-2, 8- dimethyl-purin-9-yl]-3-fluoro-phenol

The mixture from preparation 24 (435mg) was dissolved in 4 mL butanol. C,C-dicyclopropylmethylamine (215mg, 1.93 mMol) was added to the reaction mixture followed by the addition of triethylamine (0.284mL, 2.04 mMol). The reaction mixture was heated at reflux under N₂ for 18 hours. The reaction mixture was then evaporated, partitioned between 10 mL ethyl acetate and 10 mL water. The aqueous was extracted again twice with 10 mL ethyl acetate. The organics were combined, dried over magnesium sulphate, filtered and evaporated to give a brown gum (598mg, 100%). The reaction mixture was purified by column chromatography eluting from 100% Heptane to Heptane/EtOAc 20/80. The correct fractions were collected to give a pale grey foam (90mg, 11 %)

LCMS (System 4, acidic run): 2.52 mins m/z (APCI) = 367 [MH+] 1H NMR (400MHz, CD₃OD) δ =0.39-0.46 (m, 8H), 1.23-1.35 (m, 2H), 2.34 (s, 3H), 2.39 (s, 3H), 3.76 (b, 1 H), 6.76-6.81 (m, 2H), 7.18-7.27 (m, 1 H). Preparation 26 4-amino-2-fluoro -phenol

A solution of 2-fluoro-4-nitro-phenol (400 mg, 2.55 mMol) and ethanol (6 ml_) was treated with 10% Pd/C (42.6 mg). The reaction mixture was hydrogenated for 3 hours at 40 psi at room temperature. The reaction mixture was filtered through a pad of Arbocel ® with ethanol and then evaporated to dryness to give a dark solid (248mg, 85%).

¹H NMR (400MHz, CD₃OD) δ =6.29-6.31(d, 1 H), 6.39-6.43 (dd, 1 H), 6.58-6.62 (m, 1 H). GC/MS: 1.66 mins m/z (Cl) = 128 [MH+]

Preparation 27 4-(5-amino-6-chloro-2-methyl-pyrimidin-4-ylamino)-2-fluoro -phenol

A 10ml flask was charged with EtOH (3ml_). 2-methyl-4,6-dichloro-5-aminopyrimidine was added (140mg, 1.89 mMol) followed by 4-amino-2-fluoro-phenol (100mg, 1.89 mMol) and HCI (2M aq 0.787ml_, 3.78 mMol). The reaction mixture was heated at 85⁰C under N₂ for 6 hours. The reaction mixture was evaporated, partitioned between 10 ml sodium bicarbonate solution and 10 ml ethyl acetate, the aqueous was extracted again twice with 10 ml ethyl acetate, the organics were combined, dried over magnesium sulphate, filtered and evaporated to give a purple gum (308 mg, 66%).

LCMS (System 4, acidic run): 2.26 mins m/z (APCI) = 269 [MH+]

Preparation 28

4-(6-chloro-2, 8-dimethyl-purin-9-yl)-2-fluoro-phenol

A 25 mL flask (under flow N2) was charged with MeCN (5ml_) and then Et₃N (0.22OmL, 1.58 mMol). 4- (5-amino-6-chloro-2-nnethyl-pyrinnidin-4-ylannino)-2-fluoro-phenol (525 mg, 1.95 mMol) was added followed by trimethylorthoacetate (0.512 mL, 3.79 mMol). The reaction mixture was heated at 74⁰C under N₂ for 18 hours. Et₃N (91 uL, 0.655 mMol) was finally added and the reaction mixture was stirred at room temperature for one hour under N₂. The reaction mixture was evaporated, partitioned between 10 mL ethyl acetate and 10 mL water. The aqueous was extracted twice with 10 mL ethyl acetate. The organics were combined, dried over magnesium sulphate, filtered and evaporated to give a pink gum (508 mg, 88%) containing a mixture of desired product and imidoester intermediate. LCMS (System 4, acidic run): 2.24 mins m/z (APCI) = 293 [MH+]

LCMS (System 4, acidic run): 2.69 mins m/z (APCI) = 325 [imidoester intermediate]

Preparation 29

4- [6-( Dicyclopropylmethyl-amino)-2, 8- dimethyl-purin-9-yl]-2-fluoro-phenol

The mixture from preparation 28 (508mg) was dissolved in 4 mL butanol. C,C-dicyclopropylmethylamine (251 mg, 2.26 mMol) was added to the reaction mixture followed by the addition of triethylamine (0.332mL, 2.38 mMol). The reaction mixture was heated at reflux under N₂ for 18 hours. The reaction mixture was then evaporated, partitioned between 10 mL ethyl acetate and 10 mL water. The aqueous was extracted again twice with 10 mL ethyl acetate. The organics were combined, dried over magnesium sulphate, filtered and evaporated to give a brown gum (600mg, 100%). The reaction mixture was purified by column chromatography eluting from 100% Heptane to Heptane/EtOAc 50/50 to give a pale grey foam (256mg, 40%)

LCMS (System 4, acidic run): 2.41 mins m/z (APCI) = 367 [MH+] ¹H NMR (400MHz, CD₃OD) δ =0.34-0.56 (m, 8H), 1.05-1.32 (m, 2H), 2.38 (s, 3H), 2.39 (s, 3H), 3.49 (b, 1 H), 7-7.1 (m, 2H), 7.14-7.2 (m, 1 H).

Preparation 30

Tert-butyl 4-(difluoromethoxy)phenylcarbamate

To a mixture of 4-difluoromethoxyaniline (20.00 g, 126 mMol), MeCN (100 ml_) and triethylamine (35 ml_, 250 mMol) was added BoC₂O (40.98 g, 187 mMol). The reaction mixture was heated to 50⁰C and stirred for 18 hours. The reaction mixture was cooled to RT then concentrated to dryness and EtOAc (300 ml_) was added, washed with water (200 ml_), brine (200 ml_), dried over MgSO₄ then concentrated. The crude product was purified by column chromatography using 1 :1 (EtOAc/Hex) as eluent which gave the title compound (17.90 g, 54%).

¹H NMR (300MHz, CDCI₃) δ = 1.50 (s, 9H), 6.20-6.70 (t, 1 H), 6.50 (bs, 1 H), 7.04 (d, 2H), 7.36 (d, 1 H).

LCMS (System 5): 2.48 mins m/z = 204.13 [M-'bu]

Preparation 31 Terf-butyl-2-Bromo 4-(difluoromethoxy)phenylcarbamate

The terf-butyl-4-(difluoromethoxy)phenylcarbamate (17.50 g, 67.50 mMol), CCI₄ (34 mL), MeCN (18 mL) and NBS (12.61 g, 70.87 mMol) were mixed together at RT and the benzoyl peroxide (0.1 g, cat. amount) was added and the reaction mixture was heated to 60 ⁰C for 18 hours (during which time a further 0.1g of benzoyl peroxide was added). The reaction was cooled to RT, treated with sat. NaHCO₃ (50 mL), extracted with EtOAc (2 x 300 mL), washed with brine (200 mL), dried over MgSO₄ and concentrated. The crude product was purified by column chromatography using 1 :1 (EtOAc/Hex) as eluent which gave the title compound (17.4 g, 76%).

Preparation 32

2-Bromo 4-(difluoromethoxy)aniline hydrochloride

The terf-butyl-2-bromo-4(difluoromethoxy)phenyl carbamate (2.0 g, 5.9 mMol) was stirred in 2N HCI in EtOAc (10 imL) at RT for 2 hours. The reaction mixture was concentrated to dryness under vacuum which gave an off white solid (1.3 g, 76%). This was used crude in the next step.

Preparation 33

N-(2-Bromo 4-(difluoromethoxy)phenyl)-6-chloro-2-methylpyrimidine-4,5-diamine

The tert-butyl-2-bromo-4(difluoromethoxy)aniline hydrochloride (1.60 g, 5.5 mMol), 2-methyl-5-amino- 4,6-dichloropyridine (1.28 g, 7.15 mMol), EtOH (20 mL) and cone. HCI (1.1 eq., 0.51 mL) were mixed and heated to 115 ⁰C for 18 hours. The reaction was cooled to RT and concentrated to dryness then added EtOAc (50 mL) and treated with 2N NaOH solution (30 mL), then brine (30 mL), dried over Na₂SO₄ and concentrated. The solid residue was treated with EtOH/water (1 :4) and the brown solid formed was collected by filtration (1.30 g, 57%).

Preparation 34

9-(2-Bromo 4-(difluoromethoxy)phenyl)-6-chloro-2,8-dimethyl-9H-purine

The N-(2-Bromo 4-(difluoronnethoxy)phenyl)-6-chloro-2-nnethylpyrinnidine-4,5-diannine (1.0 g, 2.60 mMol), trimethylorthoacetate (0.85 g, 7.00 mMol), MeCN (10 ml_) and AcOH (3 drops) were mixed and heated to reflux for 18 hours. The reaction was cooled to RT, treated with water (10 ml_), extracted with EtOAc (2 x 30 imL), washed with brine (20 ml_), dried over Na₂SO₄ and concentrated which gave the title compound as a brown oil (1.17 g, >100%).

Preparation 35

9-(2-Bromo 4-(difluoromethoxy)phenyl)-Λ/-(dicyclopropylmethyl)-2,8-dimethyl-9H-purine-6-amine

The 9-(2-Bromo 4-(difluoromethoxy)phenyl)-6-chloro-2,8-dimethyl-9H-purine (500 mg, 1.24 mMol), C,C-dicyclopropylmethylamine hydrochloride (240 mg, 1.61 mMol), triethylamine (380 mg, 3.72 mMol) and MeCN (5.0 ml_) were heated in a microwave at 150 ⁰C for 2 hours. The reaction was treated with water (5 ml_), extracted with EtOAc (30 ml_), washed with brine (20 ml_), dried over Na₂SO₄ and concentrated. The solid residue was triturated with EtOAc/Hex (1 :15) and was collected by filtration and washed with hexane (20 ml_) which gave the title compound as a brown solid (310 mg, 52%).

LCMS (System 5): m/z = 480.09 [M+H]

Preparation 36 1-(Difluoromethoxy)-2-methoxy-4-nitrobenzene

4-Nitro-2-methoxyphenol (2.00 g, 11.8 mMol) was added to dimethylformannide (100 mL) and water (6.3 imL), that had been degassed by passage of argon (g) for 30 minutes. To this stirred solution was added sodium difluorochloroacetate (5.41 g, 35.5 mMol) followed by caesium carbonate (28.9 g, 88.3 mMol) in one portion. The reaction mixture was then heated to 8O ⁰ C for 24 hours. The reaction mixture was allowed to stand at room temperature for a further 38 hours and was then diluted with EtOAc (50 mL) and washed with water (3 x 20 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (4.20 g, 67%).

¹H NMR (300MHz, CDCI₃) δ = 3.98 (s, 3H), 6.66 (t, 2H), 7.26 (d, 1 H), 7.84-7.86 (m, 2H) LCMS (System 5): 2.2 mins

Preparation 37

4-(Difluoromethoxy)-3-methoxyaniline

Industrial methylated spirits (100 mL) and water (24 mL) were added to 1-(difluoromethoxy)-2-methoxy- 4-nitrobenzene (2.00 g, 11.8 mMol). To this stirred solution was added iron powder (1.98 g, 35.4 mMol) followed by ammonium chloride (0.38 g, 7.1 mMol) in one portion. The reaction mixture was then heated to 75⁰C for 2 hours. The reaction mixture was cooled to room temperature and passed through a plug of celite. The eluent was concentrated in vacuo to 30 mL and was then extracted with EtOAc (50 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (1.85 g, 83%), which was carried forward in crude form.

Preparation 38 δ-Chloro-Λ^^^difluoromethoxyJ-S-methoxyphenylJ^-methylpyrimidine-^S-diamine

Industrial methylated spirits (10 ml_) was added to a mixture of 1-(difluoromethoxy)-2-methoxy-5- aminobenzene (0.95 g, 5.0 mMol) and 5-amino-4,6-dichloro-2-methylpyrimidine (0.89 g, 5.0 mMol). To this stirred solution was added hydrochloric acid (0.425 ml_, 5.0 mMol) The reaction mixture was then heated to 85⁰C for 16 hours. The reaction mixture was cooled with ice cooling and the solid that precipitated out was collected by filtration. EtOAc (10 ml_) was added to this solid and the resulting slurry was adjusted to pH 12 with 1 M NaOH. The mixture was extracted with EtOAc (2 x 10 ml_). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an off-white solid (1.36 g, 82%). 1H NMR (300MHz, CDCI₃) δ = 2.38 (s, 3H), 3.87 (s, 3H), 6.63 (t, 3H), 7.05 (d, 1 H), 7.17 (dd, 1 H), 7.77 (d, 1 H)

LCMS (System 5): 2.2 mins m/z = 331 [MH+]

Preparation 39

6-Chloro-9-(4-(difluoromethoxy)-3-methoxyphenyl)-2,8-dimethyl-9H-purine

Acetonitrile (6 ml_) was added to a mixture of 6-chloro-Λ/⁴-(4-(difluoromethoxy)-3-methoxyphenyl)-2- methylpyrimidine-4,5-diamine (0.400 g, 1.21 mMol). To this stirred solution was added trimethyl orthoacetate (0.31 ml_, 2.42 mMol) and acetic acid (3 drops). The reaction mixture was heated at reflux for 17 hours and was then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (10 ml_), washed with water (1 x 10 ml_) and dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a beige solid (0.330 g, 77%).

¹H NMR (300MHz, CDCI₃) δ = 2.56 (s, 3H), 2.70 (s, 3H), 3.90 (s, 3H), 6.63 (t, 1 H), 6.94 (dd, 1 H), 6.96 (d, 1 H), 7.36 (d, 1 H)

LCMS (System 5): 2.1 mins m/z = 355 [MH+] Preparation 40 N⁴-(4-bromo-2,6-difluorophenyl)-6-chloro-2-methylpyrimidine-4,5-diamine

To a solution of 5-amino-4,6-dichloro-2-methylpyrimidine (1.78 g, 10 mMol) and 4-bromo-2,6- difluoroaniline (2.08 g, 10 mMol) in IPA (20 ml_) was added concentrated hydrochloric acid (0.85 ml_, 1OmMoI). The reaction mixture was then heated to 85⁰C for 16 hours. The reaction mixture was cooled to room temperature and a solid precipitated out. This was collected by filtration, washed with IPA (10 ml_) then dried at 5O⁰C under vacuum for 16 hours to give the title compound, as the hydrochloride salt (1.2 g, 31 %).

¹H NMR (300MHz, D₆-DMSO) δ = 2.15 (s, 3H), 6.45 (bs, 2H), 7.56 (d, 3H), 9.17 (bs, 1 H). LCMS (System 5): 1.89 mins m/z (ES+) = 349+351 [MH+]

Preparation 41

9-(4-bromo-2,6-difluorophenyl)-2,8-dimethyl-1H-purin-6(9H)-one

To N⁴-(4-bromo-2,6-difluorophenyl)-6-chloro-2-methylpyrimidine-4,5-diamine hydrochloride (1.2 g, 3.1 mMol) in acetic acid (20 ml_) was added sodium acetate (0.3 g, 3.5 mMol), followed by trimethyl orthoacetate (1 ml_). The reaction mixture was then heated to 95⁰C for 16 hour. The reaction mixture was cooled to room temperature and a solid precipitated out. This was collected by filtration, washed with acetic acid (5 ml_) then dried at 5O⁰C under vacuum for 16 hours to give the title compound (0.9 g, 84%).

¹H NMR (300MHz, D₆-DMSO) δ = 2.58 (s, 6H), 7.89 (d, 2H). LCMS (System 5): 1.75 mins m/z (ES+) = 355+357 [MH+] Preparation 42

6-Chloro-9-(4-bromo-2,6-difluorophenyl)-2,8-dimethyl-9H-purine

Phosphorus oxychloride (10 ml_) was added to 9-(4-bromo-2,6-difluorophenyl)-2,8-dimethyl-1H-purin- 6(9H)-one (0.53 g, 1.4 mMol). The reaction mixture was then heated to 95⁰C for 16 hour under a calcium chloride drying tube. The reaction mixture was cooled to room temperature, then poured onto ice/water (100 ml_). The solution was made basic with 0.88sg ammonia (15 ml_), then extracted with EtOAc (50 ml_). The organic layer was separated and washed with water (50 ml_), then brine (20 ml_). The organic layer was concentrated to give the title compound (0.53 g, 54%). 1H NMR (300MHz, CDCI₃) δ = 2.52 (s, 3H), 2.71 (s, 3H), 7.40 (d, 2H).

LCMS (System 5): 2.23 mins m/z (ES+) = 373+375 [MH+]

Preparation 43 Dicyclopropylmethyl-[9-(4-bromo-2,6-difluorophenyl)-2,8-dimethyl-9H-purin-6-yl] -amine

To 6-chloro-9-(4-bromo-2,6-difluorophenyl)-2,8-dimethyl-9H-purine (0.53 g, 1.4 mMol) in acetonitrile (5 ml_) was added C,C-dicyclopropylmethylamine (0.34 g, 3.0 mMol) followed by DMAP (1 crystal). The reaction mixture was then heated to 15O⁰C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature and a solid precipitated out. This was collected by filtration, washed with acetonitrile (1 ml_) then dried at 5O⁰C under vacuum for 16 hours to give the title compound (0.47 g, 75%).

¹H NMR (300MHz, D₆-DMSO) δ = 0.25-0.4 (m, 6H), 0.4-0.55 (m, 2H), 0.9-1.0 (m, 1 H), 2.24 (s, 3H), 2.30 (s, 3H), 7.86 (d, 2H), 7.94 (bs, 1 H).

LCMS (System 5): 2.74 mins m/z (ES+) = 448+450 [MH+] Preparation 44 4-(6-(Dicyclopropylmethylamino)-2,8-dimethyl-9H-purin-9-yl)-3,5-difluorophenol

Water (5 ml_) and NMP (5 ml_) were degassed by purging with argon for 15 min. Dicyclopropylmethyl-[9- (4-bronno-2,6-difluorophenyl)-2,8-dinnethyl-9H-purin-6-yl]-annine (0.47 g, 1.05 mMol), potassium hydroxide (0.17 g, 3.0 mMol), palladium bis-dba (0.06 g, 0.1 mMol), t-butyl X-phos (0.085 g, 0.2 mMol) were then added sequentially. This stirred reaction mixture was then heated to 95⁰C for 16 hours under Ar (g). The reaction mixture was cooled to room temperature, quenched with 1 M hydrochloric acid (aq, 10 ml_), then partitioned with EtOAc (10 ml_). The organic layer was separated and washed with water (10 ml_), then brine (10 ml_). The organic layer was concentrated to give the title compound (0.36 g, 89%).

LCMS (System 5): 1.89 mins m/z (ES+) = 386 [MH+]

Preparation 45 1-(Difluoromethoxy)-2-methoxy-5-nitrobenzene

5-Nitro-2-methoxyphenol (2.00 g, 11.8 mMol) was added to dimethylformamide (100 ml_) and water (6.3 ml_), that had been degassed by passage of argon (g) for 30 minutes. To this stirred solution was added sodium difluorochloroacetate (5.41 g, 35.5 mMol) followed by caesium carbonate (28.9 g, 88.3 mMol) in one portion. The reaction mixture was then heated to 8O ⁰ C for 24 hours. The reaction mixture was allowed to stand at room temperature for a further 38 hours and was then diluted with EtOAc (50 ml_) and washed with water (3 x 20 ml_). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (4.20 g, 67%).

¹H NMR (300MHz, CDCI₃) δ = 3.99 (s, 3H), 6.60 (t, 2H), 7.04 (d, 1 H), 8.07 (d, 1 H), 8.14 (dd, 1 H) LCMS (System 5): 2.2 mins Preparation 46 3-(Difluoromethoxy)-4-methoxyaniline

Industrial methylated spirits (100 ml_) and water (24 ml_) was added to 1-(difluoromethoxy)-2-methoxy-5- nitrobenzene (2.00 g, 11.8 mMol). To this stirred solution was added iron powder (1.98 g, 35.4 mMol) followed by ammonium chloride (0.38 g, 7.1 mMol) in one portion. The reaction mixture was then heated to 75⁰C for 2 hours. The reaction mixture was cooled to room temperature and passed through a plug of celite. The eluent was concentrated in vacuo to 30 ml_ and was then extracted with EtOAc (50 ml_). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (1.74 g, 78%), which was carried forward in crude form.

Preparation 47 δ-Chloro-Λ^^S^difluoromethoxyJ^-methoxyphenylJ^-methylpyrimidine^.S-diamine

Industrial methylated spirits (10 ml_) was added to a mixture of 1-(difluoromethoxy)-2-methoxy-5- aminobenzene (0.95 g, 5.0 mMol) and 5-amino-4,6-dichloro-2-methylpyrimidine (0.89 g, 5.0 mMol). To this stirred solution was added concentrated hydrochloric acid (0.425 ml_, 5.0 mMol). The reaction mixture was then heated to 85⁰C for 16 hours. The reaction mixture was cooled with ice cooling and the solid that precipitated out was collected by filtration. EtOAc (10 ml_) was added to this solid and the resulting slurry was adjusted to pH 12 with 1 M NaOH (aq). The mixture was extracted with EtOAc (2 x 10 ml_). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an off-white solid (1.36 g, 82%).

¹H NMR (300MHz, CDCI₃) δ = 2.34 (s, 3H), 3.84 (s, 3H), 6.70 (t, 3H), 7.03 (d, 1 H), 7.46 (dd, 1 H), 7.65 (d, 1 H) LCMS (System 5): 2.1 mins m/z = 331 [MH+]

Preparation 48 6-Chloro-9-(3-(difluoromethoxy)-4-methoxyphenyl)-2,8-dimethyl-9H-purine

Acetonitrile (6 ml_) was added to a mixture of 6-chloro-Λ/⁴-(3-(difluoromethoxy)-4-nnethoxyphenyl)-2- methylpyrimidine-4,5-diannine (0.400 g, 1.21 mMol). To this stirred solution was added trimethyl orthoacetate (0.31 ml_, 2.42 mMol) and acetic acid (3 drops). The reaction mixture was heated at reflux for 17 hours and was then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (10 ml_), washed with water (1 x 10 ml_), dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a beige solid, as a 1 :1 mixture with the ring open methyl methoxy imine (0.360 g, 84%). This was used in the next step as a mixture.

¹H NMR (300MHz, CDCI₃) δ = 1.93 (s, 3H), 2.53 (s, 3H), 2.55 (s, 3H), 2.70 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 3.97 (s, 3H), 6.58 (t, 1 H), 6.63 (t, 1 H), 6.73 (br s, 1 H), 6.93 (d, 1 H), 7.15 (d, 1 H), 7.19-7.27 (m, 2H), 7.42 (dd, 1 H), 7.60 (d, 1 H)

LCMS (System 5): 2.0 mins m/z = 355 [MH+], 2.5 mins m/z = 387 [MH+]

Preparation 49 3-Methoxy-4-nitro-phenol

Sodium (1.27 g, 55.38 mMol) was dissolved in MeOH (20 ml_). To this solution was added 3-fluoro-4- nitro-phenol (2.90 g, 18.46 mMol) in one portion. The brown reaction mixture was then heated at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, was acidified to pH 1 with 1 M HCI (aq), and was then extracted with EtOAc (2 x 50 ml_) and washed with water (3 x 20 ml_). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a brown solid that was used in crude form for the next reaction.

Preparation 50

1-(Difluoromethoxy)-3-methoxy-4-nitrobenzene

3-Methoxy-4-nitro-phenol (3.12 g, 18.46 mMol) was added to dimethylformannide (150 mL) and water (10 imL), that had been degassed by passage of argon (g) for 40 minutes. To this stirred solution was added sodium difluorochloroacetate (8.45 g, 55.4 mMol) followed by caesium carbonate (45.1 g, 138.5 mMol) in one portion. The reaction mixture was then heated to 8O ⁰C for 14 hours. The reaction mixture was then diluted with EtOAc (70 mL) and washed with water (3 x 20 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil that was used in crude form for the next reaction.

Preparation 51

4-(Difluoromethoxy)-2-methoxyaniline

Dioxane (25 mL) and water (25 mL) was added to 1-(difluoromethoxy)-3-methoxy-4-nitrobenzene (4.04 g, 18.46 mMol). To this stirred solution was added sodium hydrosulfite (19.20 g, 110.0 mMol. The reaction mixture was then heated to 3O⁰C for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with hot industrial methylated spirits (2 x 50 mL) which was concentrated in vacuo to give the title compound as a yellow oil, which was carried forward to the next reaction without further purification

¹H NMR (300MHz, CDCI₃) δ = 3.74 (brs, 2H), 3.84 (s, 3H), 6.39 (t, 3H), 6.56-6.65 (m, 3H), LCMS (System 6): 9.2 mins m/z = 190 [MH+]

Preparation 52 δ-Chloro-Λ^^^difluoromethoxyJ^-methoxyphenylJ^-methylpyrimidine-^S-diamine

Industrial methylated spirits (36 ml_) was added to a mixture of 4-(difluoromethoxy)-2-methoxyaniline (3.49 g, 18.5 mMol) and 5-amino-4,6-dichloro-2-methylpyrimidine (3.29 g, 18.5 mMol). To this stirred solution was added hydrochloric acid (1.57 ml_, 18.5 mMol). The reaction mixture was then heated to 85⁰C for 16 hours. The reaction mixture was cooled to room temperature with ice cooling and the solvent was then removed in vacuo. The residue was dissolved in EtOAc (20 ml_) and was adjusted to pH 12 with 1 M NaOH. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (2:1 to 1 :1 hexane/EtOAc) to give the title compound as a beige solid (2.56 g, 41.9 % over four steps). 1H NMR (300MHz, CDCI₃) δ = 3.52 (s, 3H), 3.37 (brs, 2H), 3.90 (s, 3H), 6.47 (t, 3H), 6.69-6.77 (m, 2H), 7.47 (brs, 1 H), 8.49 (d, 1 H)

LCMS (System 5): 2.4 mins m/z = 331 [MH+]

Preparation 53 6-Chloro-9-(4-(difluoromethoxy)-2-methoxyphenyl)-2,8-dimethyl-9H-purine

Acetonitrile (40 ml_) was added to a mixture of 6-chloro-Λ/⁴-(4-(difluoromethoxy)-2methoxyphenyl)-2- methylpyrimidine-4,5-diamine (2.56 g, 7.56 mMol). To this stirred solution was added trimethyl orthoacetate (1.86 g, 15.51 mMol) and acetic acid (30 drops). The reaction mixture was heated at reflux for 17 hours and was then allowed stir at room temperature for 72 hours. The reaction mixture was diluted with EtOAc (40 ml_), washed with water (1 x 30 ml_) and dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a black solid (2.14 g, 78%) that was used in crude form for the next reaction.

Claims

1. A compound of formula (I):

wherein:

or ,wherein the arrow heads denote the point of attachment to the phenyl moiety; R³ is H or F; with the proviso that when R¹ is Me, H or F, R² is not OCH₃;

or a pharmaceutically acceptable salt, solvate or polymorph thereof.

2. A compound as claimed in claim 1 wherein R¹ is selected from OCH₃, OC₂H₅, OCF₃, and OCHF₂.

3. A compound as claimed in claim 2 wherein R¹ is selected from OCH₃ and OCHF₂

4. A compound as claimed in claim 3 wherein R¹ is OCHF₂

5. A compound as claimed in any preceding claim wherein R² is selected from Cl, OCH₃ and H.

6. A compound as claimed in any preceding claim wherein R³ is H.

7. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 6, or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier.

8. A pharmaceutical composition as claimed in claim 7 including one or more additional therapeutic agents.

9. A compound of formula (I) as claimed in any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament.

10. A method of treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate or polymorph thereof.

11. Use of a compound of formula (I) as claimed in any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect.

12. A compound of formula (I) as claimed in any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use in the treatment of a disorder or condition where antagonism of CRF₁ receptors is known, or can be shown, to produce a beneficial effect.

13. A method as claimed in claim 10, wherein the disorder or condition is selected from sexual dysfunction, female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, anxiety with co-morbid depressive illness, affective disorder, anxiety, eating disorders, bipolar disorder and depression.

14. Use as claimed in claim 11 , wherein the disorder or condition is selected from sexual dysfunction, female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, anxiety with co-morbid depressive illness, affective disorder, anxiety, eating disorders, bipolar disorder and depression.

15. A compound as claimed in claim 12, wherein the disorder or condition is selected from sexual dysfunction, female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, anxiety with co-morbid depressive illness, affective disorder, anxiety, eating disorders, bipolar disorder and depression.

16. A method as claimed in claim 13 wherein the disorder or condition is selected from female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder.

17. Use as claimed in claim 14 wherein the disorder or condition is selected from female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder.

18. A compound as claimed in claim 15 wherein the disorder or condition is selected from female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder.